U.S. patent application number 10/484652 was filed with the patent office on 2005-03-03 for pyrrole-type compounds, compositions, and methods for treating cancer, treating viral diseases and causing immunosuppression.
Invention is credited to Attardo, Giorgio, Johnson, Roy A., Murthy, Madiraju S.R., Shore, Gordon C..
Application Number | 20050049292 10/484652 |
Document ID | / |
Family ID | 23182716 |
Filed Date | 2005-03-03 |
United States Patent
Application |
20050049292 |
Kind Code |
A1 |
Shore, Gordon C. ; et
al. |
March 3, 2005 |
Pyrrole-type compounds, compositions, and methods for treating
cancer, treating viral diseases and causing immunosuppression
Abstract
The present invention relates to novel Pyrrole-Type compounds,
compositions comprising Pyrrole-Type compounds, and methods useful
for treating or preventing cancer or a neoplastic disorder
comprising administering a Pyrrole-Type compound. The compounds,
compositions, and methods of the invention are also useful for
inhibiting the growth of a cancer cell or neoplastic cell. The
present invention also relates to novel Pyrrole-Type compounds,
compositions, and methods useful for treating or preventing a viral
infection. The compounds, compositions, and methods of the
invention are also useful for inhibiting the replication and/or
infectivity of a virus. The present invention also relates to novel
Pyrrole-Type compounds, compositions, and methods useful for
causing immunosuppression. The present invention also relates to
novel Pyrrole-Type compounds, compositions, and methods useful for
treating or preventing an autoimmune disease.
Inventors: |
Shore, Gordon C.; (Montreal,
CA) ; Murthy, Madiraju S.R.; (Brossard, CA) ;
Johnson, Roy A.; (Sausalito, CA) ; Attardo,
Giorgio; (Laval, CA) |
Correspondence
Address: |
JONES DAY
222 EAST 41ST ST
NEW YORK
NY
10017
US
|
Family ID: |
23182716 |
Appl. No.: |
10/484652 |
Filed: |
July 26, 2004 |
PCT Filed: |
July 18, 2002 |
PCT NO: |
PCT/CA02/01104 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60305870 |
Jul 18, 2001 |
|
|
|
Current U.S.
Class: |
514/410 ;
548/421 |
Current CPC
Class: |
A61P 17/06 20180101;
C07D 403/10 20130101; A61P 1/04 20180101; A61P 7/04 20180101; A61P
25/00 20180101; A61P 13/12 20180101; A61P 7/06 20180101; A61P 21/04
20180101; A61P 35/00 20180101; A61P 37/06 20180101; C07D 207/44
20130101; C07D 403/14 20130101; A61P 37/08 20180101; A61P 3/10
20180101; A61P 35/02 20180101; A61P 31/14 20180101; C07D 207/36
20130101; C07D 405/14 20130101; A61P 29/00 20180101; C07D 409/14
20130101 |
Class at
Publication: |
514/410 ;
548/421 |
International
Class: |
A61K 031/407; C07D
491/14 |
Claims
What is claimed is:
1. A compound having the general Formula (I): 64or a
pharmaceutically acceptable salt thereof, wherein: each R.sub.1 is
independently selected from the group consisting of --H,
--CH.sub.3, --CH.sub.2C.sub.6H.sub.5, --C(O)OC(CH.sub.3).sub.3, and
--C(O)OCH.sub.2C.sub.6H.sub.5; and n is an integer ranging from 1
and 5.
2. The compound of claim 1, wherein: each R.sub.1 is independently
selected from the group consisting of --H and --CH.sub.3; and n is
an integer ranging from 1 to 5.
3. The compound of claim 2, wherein: R.sub.1 is --H; and n is an
integer ranging from 1 to 3.
4. A compound having the general Formula (II): 65or a
pharmaceutically acceptable salt thereof, wherein: each R.sub.1 is
independently selected from the group consisting of --H,
--CH.sub.3, --CH.sub.2C.sub.6H.sub.5, --C(O)OC(CH.sub.3).sub.3, and
--C(O)OCH.sub.2C.sub.6H.sub.5; and n is an integer ranging from 1
and 5.
5. The compound of claim 4, wherein: each R.sub.1 is independently
selected from the group consisting of --H and --CH.sub.3; and n is
an integer ranging from 1 to 5.
6. The compound of claim 5, wherein: R.sub.1 is --H; and n is an
integer ranging from 1 to 3.
7. A compound having the general Formula (III): 66or a
pharmaceutically acceptable salt thereof, wherein: each R.sub.1 is
independently selected from the group consisting of --H,
--CH.sub.3, --CH.sub.2C.sub.6H5, --C(O)OC(CH.sub.3).sub.3, and
--C(O)OCH.sub.2C.sub.6H.sub.5; R.sub.2 is a C.sub.1-C.sub.10
straight chain alky or --CH.sub.2C.sub.6H.sub.5, the
--CH.sub.2C.sub.6H.sub.5 being unsubstituted or substituted on the
phenyl with one or more methoxyl, halogen, methyl, nitro,
trifluoromethyl, or methoxylcarbonyl groups; R.sub.3 is --CH.sub.3,
--CH.sub.2CH.sub.3, or --C.sub.6H.sub.5; R.sub.4 is --H, a
C.sub.1-C.sub.15 straight chain alkyl, -2-pyrrolyl, -3-pyrrolyl,
-2-furanyl, -3-furanyl, or --C.sub.6H.sub.5, the --C.sub.6H.sub.5
being unsubstituted or substituted with one or more methyl,
methoxyl, halogen, trifluoromethyl, or methoxycarbonyl groups;
R.sub.5 is --H, a C.sub.1-C.sub.12 straight chain alkyl,
i-C.sub.3H.sub.7, or --C.sub.6H.sub.5; R.sub.6 is --H, a
C.sub.1-C.sub.12 straight chain alkyl, i-C.sub.3H.sub.7,
C.sub.3-C.sub.7 cycloalkyl, or --C.sub.6H.sub.5.
8. The compound of claim 7, wherein: R.sub.1 is --H; R.sub.2 is
--CH.sub.3, --CH.sub.2C.sub.6H.sub.5; R.sub.3 is --CH.sub.3;
R.sub.4 is --H or a C.sub.1-C.sub.15 straight chain alkyl; R.sub.5
is --H or a C.sub.1-C.sub.5 straight chain alkyl; and R.sub.6 is
--H or --CH.sub.3;
9. The compound of claim 8, wherein: R.sub.1 is --H; R.sub.2 and
R.sub.3 is --CH.sub.3; R.sub.4 is --H or
--(CH.sub.2).sub.14CH.sub.3; R.sub.5is --H or -n-C.sub.5H.sub.11;
and R.sub.6is --H.
10. A compound having the general Formula (IV): 67or a
pharmaceutically acceptable salt thereof, wherein: each R.sub.1 is
independently selected from the group consisting of --H,
--CH.sub.3, --CH.sub.2C.sub.6H.sub.5, --C(O)OC(CH.sub.3).sub.3, and
--C(O)OCH.sub.2C.sub.6H.sub.5; R.sub.2 is a C.sub.1-C.sub.10
straight chain alkyl, or --CH.sub.2C.sub.6H.sub.5, the
--CH.sub.2C.sub.6H.sub.5 being unsubstituted or substituted on the
phenyl with one or more methoxyl, halogen, methyl, nitro,
trifluoromethyl, or methoxylcarbonyl groups; R.sub.3 is --CH.sub.3,
--CH.sub.2CH.sub.3, or --C.sub.6H.sub.5; R.sub.4 is a
C.sub.1-C.sub.15 straight chain alkyl, -2-pyrrolyl, -3-pyrrolyl,
-2-furanyl, -3-furanyl, or --C.sub.6H.sub.5, the --C.sub.6H.sub.5
being unsubstituted or substituted with one or more methyl,
methoxyl, halogen, trifluoromethyl, or methoxycarbonyl groups,
R.sub.8 is --H, --CH.sub.3, --CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.- 3, or --(CH.sub.2).sub.3CH.sub.3; and m
is 1 to 4.
11. The compound of claim 10, wherein: R.sub.1 is --H; R.sub.2 is
--CH.sub.3 or --CH.sub.2C.sub.6H.sub.5; R.sub.3 is --CH.sub.3;
R.sub.4 is --H or a C.sub.1-C.sub.15 straight chain alkyl; R.sub.8
is --H or --CH.sub.3; and m is 2.
12. The compound of claim 11, wherein: R.sub.1 is --H; R.sub.2,
R.sub.3, and R4 is --CH.sub.3; R.sub.8 is --H or CH.sub.3; and m is
2.
13. A compound having the general Formula (V): 68or a
pharmaceutically acceptable salt thereof, wherein: each R.sub.1 is
independently selected from the group consisting of --H,
--CH.sub.3, --CH.sub.2C.sub.6H.sub.5, --C(O)OC(CH.sub.3).sub.3, and
--C(O)OCH.sub.2C.sub.6H.sub.5; R.sub.2 is a C.sub.1-C.sub.10
straight chain alkyl, or --CH.sub.2C.sub.6H.sub.5, the
--CH.sub.2C.sub.6H.sub.5 being unsubstituted substituted on the
phenyl with one or more methoxyl, halogen, methyl, nitro,
trifluoromethyl, or methoxylcarbonyl groups; R.sub.3 is --CH.sub.3,
--CH.sub.2CH.sub.3, or --C.sub.6H.sub.5; R.sub.7 is --H, a
C.sub.1-C.sub.10 straight chain alkyl, or --CH(CH.sub.3).sub.2; and
n is 4 to 8.
14. The compound of claim 13, wherein: R.sub.1 is --H; R.sub.2 is
--CH.sub.3, or --CH.sub.2C.sub.6H.sub.5; R.sub.3 is --CH.sub.3;
R.sub.7 is --H or a C.sub.1-C.sub.4 straight or branched chain
alkyl; and n is 4.
15. The compound of claim 14, wherein: R.sub.1 is --H; R.sub.2 and
R.sub.3 is --CH.sub.3; R.sub.7 is --H, --C.sub.2H.sub.5, or
-n-C.sub.4H.sub.9; and n is 4.
16. A compound of general Formula (VI): 69or a pharmaceutically
acceptable salt thereof, wherein: R.sub.2 is a C.sub.1-C.sub.10
straight chain alkyl or --CH.sub.2C.sub.6H.sub.5; R.sub.3 is a
C.sub.1-C.sub.10 straight chain alkyl, --CH(CH.sub.3).sub.2,
--CH(CH.sub.3)CH.sub.2CH.sub.- 3,
--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.3,
--CH(OH)CH.sub.2CH.sub.2CH.sub.- 3,
--CH(Cl)CH.sub.2CH.sub.2CH.sub.3, or --CH.sub.2C.sub.6H.sub.5; and
n is 1 to 5.
17. The compound of claim 16, wherein: R.sub.2 is --CH.sub.3, or
--CH.sub.2C.sub.6H.sub.5; R.sub.3 is --H or C.sub.1-C.sub.4
straight or branched chain alkyl; and n is 1.
18. The compound of claim 17, wherein: R.sub.2 is --CH.sub.3;
R.sub.3 is -n-C.sub.4H.sub.9; and n is 1.
19. A compound of general Formula (VII): 70or a pharmaceutically
acceptable salt thereof, wherein: R.sub.2 is a C.sub.1-C.sub.10
straight chain alkyl or --CH.sub.2C.sub.6H.sub.5; and R.sub.4 is
--H or a C.sub.1-C.sub.15 straight chain alkyl.
20. The compound of claim 19, wherein: R.sub.2 is --CH.sub.3 or
--CH.sub.2C.sub.6H.sub.5; and R.sub.4 is --H, --CH.sub.3, or
(CH.sub.2).sub.14CH.sub.3.
21. The compound of claim 20, wherein: R.sub.2 is --CH.sub.3; and
R.sub.4 is --H, --CH.sub.3, or (CH.sub.2).sub.14CH.sub.3.
22. A compound of general Formula (VIII): 71or a pharmaceutically
acceptable salt thereof, wherein: R.sub.2 is a C.sub.1-C.sub.10
straight chain alkyl or --CH.sub.2C.sub.6H.sub.5; R.sub.4 is --H or
a C.sub.1-C.sub.10 straight chain alkyl; R.sub.5 is --H or a
C.sub.1-C.sub.10 straight chain alkyl; and m is 1 to 4.
23. The compound of claim 22, wherein: R.sub.2 is --CH.sub.3 or
--CH.sub.2C6H.sub.5; R.sub.4 and R.sub.5 is --H or --CH.sub.3; and
m is 2.
24. The compound of claim 23, wherein: R.sub.2 and R.sub.5 is
--CH.sub.3; R.sub.4 is --H or --CH.sub.3; and m is 2.
25. A compound of general Formula (IX): 72or a pharmaceutically
acceptable salt thereof, wherein: R.sub.1 is --H, --CH.sub.3,
--SO.sub.2-4-methylphenyl, --CH.sub.2C.sub.6H.sub.5,
--Si(R.sub.5R.sub.6R.sub.7), --CH.sub.2OCH.sub.2CH.sub.2SiCH.sub.3,
--C(O)OC(CH.sub.3).sub.3, or --C(O)CH.sub.2C.sub.6H.sub.5;
R.sub.2is --CH.sub.3, --CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.3, or --CH.sub.2C.sub.6H.sub.5; R.sub.3 is
--H or Cl; R.sub.4 is --H or a C.sub.1-C.sub.10 straight chain
alkyl; R.sub.5 is a C.sub.1-C.sub.4 straight or branched chain
alkyl or --C.sub.6H.sub.5; R.sub.6 is a C.sub.1-C.sub.3 straight or
branched chain alkyl; R.sub.7 is a C.sub.1-C.sub.3 straight or
branched chain alkyl; and n is 1 to 5.
26. The compound of claim 25, wherein: R.sub.1 is --H; R.sub.2 is
--CH.sub.3 or --CH.sub.2C.sub.6H.sub.5; R.sub.3 is --H; R.sub.4 is
--H or a C.sub.1-C.sub.4 straight or branched chain alkyl; and n is
1 to 3.
27. The compound of claim 26, wherein: R.sub.1 is --H; R.sub.2 is
--CH.sub.3; R.sub.3 is --H; R.sub.4 is --C.sub.4H.sub.9; and n is
1.
28. The compound of claim 26, wherein: R.sub.1 is --H; R.sub.2 is
--CH.sub.3; R.sub.3 is --H; R.sub.4 is --C.sub.2H.sub.5; and n is
3.
29. A compound of general Formula (X): 73or a pharmaceutically
acceptable salt thereof, wherein: R.sub.1 is --H, --CH.sub.3,
--CH.sub.2C.sub.6H.sub.5, --COCH.sub.3, --C(O)OC(CH.sub.3).sub.3,
or --C(O)CH.sub.2C.sub.6H.sub.5; R.sub.2 is a C.sub.1-C.sub.10
straight chain alkyl or --CH.sub.2C.sub.6H.sub.5, the
--CH.sub.2C.sub.6H.sub.5 being unsubstituted or substituted with
one or more halo, methoxyl, methyl, methoxycarbonyl, or nitro
groups; R.sub.3 is --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5, or
--C(O)OC(CH.sub.3).sub.3; R.sub.4 is --H or --CH.sub.3; R.sub.5 is
--H, --CH.sub.3, --OCH.sub.3, --F, --Cl, --Br, --I, --CN,
--NH.sub.2; --NH(C.sub.1-C.sub.3 straight or branched chain alkyl),
--NHCOCH.sub.3, --NO.sub.2, --COOH, --COOR.sub.6, --OH, or
--OCH.sub.2C.sub.6H.sub.5; and R.sub.6 is a C.sub.1-C.sub.6
straight chain alkyl.
30. The compound of claim 29, wherein: R.sub.1 is --H; R.sub.2 is
--CH.sub.3 or --CH.sub.2C.sub.6H.sub.5; R.sub.3 is --H; R.sub.4 is
--H or --CH.sub.3; R.sub.5 is --H, halogen, or --COOR.sub.6; and
R.sub.6 is --CH.sub.3.
31. The compound of claim 30, wherein: R.sub.1 is --H; R.sub.2 is
--CH.sub.3; R.sub.3 is --H; R.sub.4 is --H or --CH.sub.3; and
R.sub.5 is --H.
32. A compound of general Formula (XI): 74or a pharmaceutically
acceptable salt thereof, wherein: R.sub.1 is --H, --CH.sub.3,
--CH.sub.2C.sub.6H.sub.5, --COCH.sub.3, --C(O)OC(CH.sub.3).sub.3,
or --C(O)CH.sub.2C.sub.6H.sub.5; R.sub.2 is a C.sub.1-C.sub.10
straight chain alkyl or --CH.sub.2C.sub.6H.sub.5; R.sub.3 is --H,
--CH.sub.3, --CH.sub.2C.sub.6H.sub.5, --C(O)OC(CH.sub.3).sub.3, or
--C(O)CH.sub.2C.sub.6H.sub.5; R.sub.4 is --H or --CH.sub.3; R.sub.5
is --H, a C.sub.1-C.sub.10 straight chain alkyl, --OR.sub.6, --F,
--Cl, --Br, --I, --CN, --COOH, --COOR.sub.6, --NH.sub.2;
--NHCOR.sub.6, --NO.sub.2, --OH, or --OCH.sub.2C.sub.6H.sub.5; and
R.sub.6 is a C.sub.1-C.sub.6 straight chain alkyl.
33. The compound of claim 32, wherein: R.sub.1 is --H; R.sub.2 is
--CH.sub.3 or --CH.sub.2C.sub.6H.sub.5; R.sub.3 is --H; R.sub.4 is
--H or --CH.sub.3; R.sub.5 is --H, --CH.sub.3, halogen, or
COOR.sub.6; and R.sub.6 is --CH.sub.3.
34. The compound of claim 33, wherein: R.sub.1 is --H; R.sub.2 is
--CH.sub.3; R.sub.3 is --H; R.sub.4 is --CH.sub.3; and R.sub.5 is
--H or Cl.
35. A compound of general Formula (XII): 75or a pharmaceutically
acceptable salt thereof, wherein: R.sub.1 is --H, --CH.sub.3,
--CH.sub.2C.sub.6H.sub.5, or --C(O)OC(CH.sub.3).sub.3; R.sub.2 is a
C.sub.1-C.sub.10 straight chain alkyl or --CH.sub.2C.sub.6H.sub.5;
R.sub.3 is --H, --SO.sub.2CH.sub.3, --SO.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, --COCH.sub.3,
--CO(CH.sub.2).sub.4CH.sub.3, --CO(CH.sub.2).sub.8,CH.sub.3,
--COC.sub.6H.sub.5, --CO-4-(NHCOC.sub.6H.sub.5)C.sub.6H.sub.4,
--CO-2-pyridyl, --CO-2-napthyl, --CO-2-quinolyl,
--CO-6-(NHCO(CH.sub.2).sub.4CH.sub.3)-2-- quinolyl,
--CO-2-pyrrolyl, -2-CO-2-indolyl, --CO-1-methyl-2-indolyl,
--CO-2-benzofuranyl, --CO-2-benzothiophenyl,
--CO-3-methyl-2-indenyl, or --CO--R.sub.4-2-indolyl; and R.sub.4 is
-5-OCH.sub.3, -6-OH-7-OCH.sub.3, -5-NHCONH.sub.2,
5-NHCOC.sub.6H.sub.5, -5-NHCO-indolyl, -5-NHCO-2-benzofuranyl,
-5-NHCO-5(NHCONH.sub.2)-2-indolyl, or
-5-NHCO-5(NHCOC.sub.6H.sub.5)-2-indolyl.
36. The compound of claim 35, wherein: R.sub.1 is --H; R.sub.2 is
--CH.sub.3 or --CH.sub.2C.sub.6H.sub.5; R.sub.3 is --H,
--COCH.sub.3, --CO-2-quinolyl,
--CO-6-(NHCO(CH.sub.2).sub.4CH.sub.3)-2-quinolyl, -2-CO-2-indolyl,
or --CO--R.sub.4-2-indolyl; and R.sub.4 is -5-NHCO-indolyl,
-5-NHCO-2-benzofuranyl, or -5-NHCO-5(NHCONH.sub.2)-2-ind- olyl.
37. The compound of claim 36, wherein: R.sub.1 is --H; R.sub.2 is
--CH.sub.3; R.sub.3 is --H, --COCH.sub.3, or
--CO--R.sub.4-2-indolyl; and; R.sub.4 is -5-NHCO-indolyl.
38. A compound of general Formula (XIII): 76or a pharmaceutically
acceptable salt thereof, wherein: each R.sub.1 is independently
selected from the group consisting of --H, --CH.sub.3,
--CH.sub.2C.sub.6H.sub.5, --C(O)OC(CH.sub.3).sub.3, or
--C(O)OCH.sub.2C.sub.6H.sub.5; R.sub.2 is --H or a C.sub.1-C.sub.10
straight chain alkyl; and n is 1 to 4.
39. The compound of claim 38, wherein: R.sub.1 is --H; R.sub.2 is
--H or --CH.sub.3; and n is 1 to 4.
40. The compound of claim 39, wherein: R.sub.1 is --H; R.sub.2 is
--H or --CH.sub.3; and n is 2.
41. A method for treating or preventing cancer or neoplastic
disease comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 1.
42. A method for treating or preventing cancer or neoplastic
disease comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 2.
43. A method for treating or preventing cancer or neoplastic
disease comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 3.
44. A method for treating or preventing cancer or neoplastic
disease comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 4.
45. A method for treating or preventing cancer or neoplastic
disease comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 5.
46. A method for treating or preventing cancer or neoplastic
disease comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 6.
47. A method for treating or preventing cancer or neoplastic
disease comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 7.
48. A method for treating or preventing cancer or neoplastic
disease comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 8.
49. A method for treating or preventing cancer or neoplastic
disease comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 9.
50. A method for treating or preventing cancer or neoplastic
disease comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 10.
51. A method for treating or preventing cancer or neoplastic
disease comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 11.
52. A method for treating or preventing cancer or neoplastic
disease comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 12.
53. A method for treating or preventing cancer or neoplastic
disease comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 13.
54. A method for treating or preventing cancer or neoplastic
disease comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 14.
55. A method for treating or preventing cancer or neoplastic
disease comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 15.
56. A method for treating or preventing cancer or neoplastic
disease comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 16.
57. A method for treating or preventing cancer or neoplastic
disease comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 17.
58. A method for treating or preventing cancer or neoplastic
disease comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 18.
59. A method for treating or preventing cancer or neoplastic
disease comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 19.
60. A method for treating or preventing cancer or neoplastic
disease comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 20.
61. A method for treating or preventing cancer or neoplastic
disease comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 21.
62. A method for treating or preventing cancer or neoplastic
disease comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 22.
63. A method for treating or preventing cancer or neoplastic
disease comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 23.
64. A method for treating or preventing cancer or neoplastic
disease comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 24.
65. A method for treating or preventing cancer or neoplastic
disease comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 25.
66. A method for treating or preventing cancer or neoplastic
disease comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 26.
67. A method for treating or preventing cancer or neoplastic
disease comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 27.
68. A method for treating or preventing cancer or neoplastic
disease comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 28.
69. A method for treating or preventing cancer or neoplastic
disease comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 29.
70. A method for treating or preventing cancer or neoplastic
disease comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 30.
71. A method for treating or preventing cancer or neoplastic
disease comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 31.
72. A method for treating or preventing cancer or neoplastic
disease comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 32.
73. A method for treating or preventing cancer or neoplastic
disease comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 33.
74. A method for treating or preventing cancer or neoplastic
disease comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 34.
75. A method for treating or preventing cancer or neoplastic
disease comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 35.
76. A method for treating or preventing cancer or neoplastic
disease comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 36.
77. A method for treating or preventing cancer or neoplastic
disease comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 37.
78. A method for treating or preventing cancer or neoplastic
disease comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 38.
79. A method for treating or preventing cancer or neoplastic
disease comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 39.
80. A method for treating or preventing cancer or neoplastic
disease comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 40.
81. A method for inhibiting the growth of a cancer cell or
neoplastic cell comprising contacting a cancer cell or neoplastic
cell with an effective amount of the compound of claim 1.
82. A method for inhibiting the growth of a cancer cell or
neoplastic cell comprising contacting a cancer cell or neoplastic
cell with an effective amount of the compound of claim 2.
83. A method for inhibiting the growth of a cancer cell or
neoplastic cell comprising contacting a cancer cell or neoplastic
cell with an effective amount of the compound of claim 3.
84. A method for inhibiting the growth of a cancer cell or
neoplastic cell comprising contacting a cancer cell or neoplastic
cell with an effective amount of the compound of claim 4.
85. A method for inhibiting the growth of a cancer cell or
neoplastic cell comprising contacting a cancer cell or neoplastic
cell with an effective amount of the compound of claim 5.
86. A method for inhibiting the growth of a cancer cell or
neoplastic cell comprising contacting a cancer cell or neoplastic
cell with an effective amount of the compound of claim 6.
87. A method for inhibiting the growth of a cancer cell or
neoplastic cell comprising contacting a cancer cell or neoplastic
cell with an effective amount of the compound of claim 7.
88. A method for inhibiting the growth of a cancer cell or
neoplastic cell comprising contacting a cancer cell or neoplastic
cell with an effective amount of the compound of claim 8.
89. A method for inhibiting the growth of a cancer cell or
neoplastic cell comprising contacting a cancer cell or neoplastic
cell with an effective amount of the compound of claim 9.
90. A method for inhibiting the growth of a cancer cell or
neoplastic cell comprising contacting a cancer cell or neoplastic
cell with an effective amount of the compound of claim 10.
91. A method for inhibiting the growth of a cancer cell or
neoplastic cell comprising contacting a cancer cell or neoplastic
cell with an effective amount of the compound of claim 11.
92. A method for inhibiting the growth of a cancer cell or
neoplastic cell comprising contacting a cancer cell or neoplastic
cell with an effective amount of the compound of claim 12.
93. A method for inhibiting the growth of a cancer cell or
neoplastic cell comprising contacting a cancer cell or neoplastic
cell with an effective amount of the compound of claim 13.
94. A method for inhibiting the growth of a cancer cell or
neoplastic cell comprising contacting a cancer cell or neoplastic
cell with an effective amount of the compound of claim 14.
95. A method for inhibiting the growth of a cancer cell or
neoplastic cell comprising contacting a cancer cell or neoplastic
cell with an effective amount of the compound of claim 15.
96. A method for inhibiting the growth of a cancer cell or
neoplastic cell comprising contacting a cancer cell or neoplastic
cell with an effective amount of the compound of claim 16.
97. A method for inhibiting the growth of a cancer cell or
neoplastic cell comprising contacting a cancer cell or neoplastic
cell with an effective amount of the compound of claim 17.
98. A method for inhibiting the growth of a cancer cell or
neoplastic cell comprising contacting a cancer cell or neoplastic
cell with an effective amount of the compound of claim 18.
99. A method for inhibiting the growth of a cancer cell or
neoplastic cell comprising contacting a cancer cell or neoplastic
cell with an effective amount of the compound of claim 19.
100. A method for inhibiting the growth of a cancer cell or
neoplastic cell comprising contacting a cancer cell or neoplastic
cell with an effective amount of the compound of claim 20.
101. A method for inhibiting the growth of a cancer cell or
neoplastic cell comprising contacting a cancer cell or neoplastic
cell with an effective amount of the compound of claim 21.
102. A method for inhibiting the growth of a cancer cell or
neoplastic cell comprising contacting a cancer cell or neoplastic
cell with an effective amount of the compound of claim 22.
103. A method for inhibiting the growth of a cancer cell or
neoplastic cell comprising contacting a cancer cell or neoplastic
cell with an effective amount of the compound of claim 23.
104. A method for inhibiting the growth of a cancer cell or
neoplastic cell comprising contacting a cancer cell or neoplastic
cell with an effective amount of the compound of claim 24.
105. A method for inhibiting the growth of a cancer cell or
neoplastic cell comprising contacting a cancer cell or neoplastic
cell with an effective amount of the compound of claim 25.
106. A method for inhibiting the growth of a cancer cell or
neoplastic cell comprising contacting a cancer cell or neoplastic
cell with an effective amount of the compound of claim 26.
107. A method for inhibiting the growth of a cancer cell or
neoplastic cell comprising contacting a cancer cell or neoplastic
cell with an effective amount of the compound of claim 27.
108. A method for inhibiting the growth of a cancer cell or
neoplastic cell comprising contacting a cancer cell or neoplastic
cell with an effective amount of the compound of claim 28.
109. A method for inhibiting the growth of a cancer cell or
neoplastic cell comprising contacting a cancer cell or neoplastic
cell with an effective amount of the compound of claim 29.
110. A method for inhibiting the growth of a cancer cell or
neoplastic cell comprising contacting a cancer cell or neoplastic
cell with an effective amount of the compound of claim 30.
111. A method for inhibiting the growth of a cancer cell or
neoplastic cell comprising contacting a cancer cell or neoplastic
cell with an effective amount of the compound of claim 31.
112. A method for inhibiting the growth of a cancer cell or
neoplastic cell comprising contacting a cancer cell or neoplastic
cell with an effective amount of the compound of claim 32.
113. A method for inhibiting the growth of a cancer cell or
neoplastic cell comprising contacting a cancer cell or neoplastic
cell with an effective amount of the compound of claim 33.
114. A method for inhibiting the growth of a cancer cell or
neoplastic cell comprising contacting a cancer cell or neoplastic
cell with an effective amount of the compound of claim 34.
115. A method for inhibiting the growth of a cancer cell or
neoplastic cell comprising contacting a cancer cell or neoplastic
cell with an effective amount of the compound of claim 35.
116. A method for inhibiting the growth of a cancer cell or
neoplastic cell comprising contacting a cancer cell or neoplastic
cell with an effective amount of the compound of claim 36.
117. A method for inhibiting the growth of a cancer cell or
neoplastic cell comprising contacting a cancer cell or neoplastic
cell with an effective amount of the compound of claim 37.
118. A method for inhibiting the growth of a cancer cell or
neoplastic cell comprising contacting a cancer cell or neoplastic
cell with an effective amount of the compound of claim 38.
119. A method for inhibiting the growth of a cancer cell or
neoplastic cell comprising contacting a cancer cell or neoplastic
cell with an effective amount of the compound of claim 39.
120. A method for inhibiting the growth of a cancer cell or
neoplastic cell comprising contacting a cancer cell or neoplastic
cell with an effective amount of the compound of claim 40.
121. A method for treating or preventing a viral infection in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 1.
122. A method for treating or preventing a viral infection in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 2.
123. A method for treating or preventing a viral infection in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 3.
124. A method for treating or preventing a viral infection in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 4.
125. A method for treating or preventing a viral infection in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 5.
126. A method for treating or preventing a viral infection in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 6.
127. A method for treating or preventing a viral infection in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 7.
128. A method for treating or preventing a viral infection in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 8.
129. A method for treating or preventing a viral infection in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 9.
130. A method for treating or preventing a viral infection in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 10.
131. A method for treating or preventing a viral infection in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 11.
132. A method for treating or preventing a viral infection in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 12.
133. A method for treating or preventing a viral infection in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 13.
134. A method for treating or preventing a viral infection in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 14.
135. A method for treating or preventing a viral infection in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 15.
136. A method for treating or preventing a viral infection in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 16.
137. A method for treating or preventing a viral infection in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 17.
138. A method for treating or preventing a viral infection in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 18.
139. A method for treating or preventing a viral infection in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the 10 compound of
claim 19.
140. A method for treating or preventing a viral infection in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 20.
141. A method for treating or preventing a viral infection in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 21.
142. A method for treating or preventing a viral infection in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 22.
143. A method for treating or preventing a viral infection in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 23.
144. A method for treating or preventing a viral infection in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 24.
145. A method for treating or preventing a viral infection in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 25.
146. A method for treating or preventing a viral infection in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 26.
147. A method for treating or preventing a viral infection in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 27.
148. A method for treating or preventing a viral infection in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 28.
149. A method for treating or preventing a viral infection in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 29.
150. A method for treating or preventing a viral infection in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 30.
151. A method for treating or preventing a viral infection in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 31.
152. A method for treating or preventing a viral infection in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 32.
153. A method for treating or preventing a viral infection in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 33.
154. A method for treating or preventing a viral infection in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 34.
155. A method for treating or preventing a viral infection in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 35.
156. A method for treating or preventing a viral infection in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 36.
157. A method for treating or preventing a viral infection in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 37.
158. A method for treating or preventing a viral infection in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 38.
159. A method for treating or preventing a viral infection in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 39.
160. A method for treating or preventing a viral infection in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 40.
161. A method for inhibiting the replication or infectivity of a
virus comprising a contacting a virus or a virus-infected cell with
an effective amount of the compound of claim 1.
162. A method for inhibiting the replication or infectivity of a
virus comprising a contacting a virus or a virus-infected cell with
an effective amount of the compound of claim 2.
163. A method for inhibiting the replication or infectivity of a
virus comprising a contacting a virus or a virus-infected cell with
an effective amount of the compound of claim 3.
164. A method for inhibiting the replication or infectivity of a
virus comprising a contacting a virus or a virus-infected cell with
an effective amount of the compound of claim 4.
165. A method for inhibiting the replication or infectivity of a
virus comprising a contacting a virus or a virus-infected cell with
an effective amount of the compound of claim 5.
166. A method for inhibiting the replication or infectivity of a
virus comprising a contacting a virus or a virus-infected cell with
an effective amount of the compound of claim 6.
167. A method for inhibiting the replication or infectivity of a
virus comprising a contacting a virus or a virus-infected cell with
an effective amount of the compound of claim 7.
168. A method for inhibiting the replication or infectivity of a
virus comprising a contacting a virus or a virus-infected cell with
an effective amount of the compound of claim 8.
169. A method for inhibiting the replication or infectivity of a
virus comprising a contacting a virus or a virus-infected cell with
an effective amount of the compound of claim 9.
170. A method for inhibiting the replication or infectivity of a
virus comprising a contacting a virus or a virus-infected cell with
an effective amount of the compound of claim 10.
171. A method for inhibiting the replication or infectivity of a
virus comprising a contacting a virus or a virus-infected cell with
an effective amount of the compound of claim 11.
172. A method for inhibiting the replication or infectivity of a
virus comprising a contacting a virus or a virus-infected cell with
an effective amount of the compound of claim 12.
173. A method for inhibiting the replication or infectivity of a
virus comprising a contacting a virus or a virus-infected cell with
an effective amount of the compound of claim 13.
174. A method for inhibiting the replication or infectivity of a
virus comprising a contacting a virus or a virus-infected cell with
an effective amount of the compound of claim 14.
175. A method for inhibiting the replication or infectivity of a
virus comprising a contacting a virus or a virus-infected cell with
an effective amount of the compound of claim 15.
176. A method for inhibiting the replication or infectivity of a
virus comprising a contacting a virus or a virus-infected cell with
an effective amount of the compound of claim 16.
177. A method for inhibiting the replication or infectivity of a
virus comprising a contacting a virus or a virus-infected cell with
an effective amount of the compound of claim 17.
178. A method for inhibiting the replication or infectivity of a
virus comprising a contacting a virus or a virus-infected cell with
an effective amount of the compound of claim 18.
179. A method for inhibiting the replication or infectivity of a
virus comprising a contacting a virus or a virus-infected cell with
an effective amount of the compound of claim 19.
180. A method for inhibiting the replication or infectivity of a
virus comprising a contacting a virus or a virus-infected cell with
an effective amount of the compound of claim 20.
181. A method for inhibiting the replication or infectivity of a
virus comprising a contacting a virus or a virus-infected cell with
an effective amount of the compound of claim 21.
182. A method for inhibiting the replication or infectivity of a
virus comprising a contacting a virus or a virus-infected cell with
an effective amount of the compound of claim 22.
183. A method for inhibiting the replication or infectivity of a
virus comprising a contacting a virus or a virus-infected cell with
an effective amount of the compound of claim 23.
184. A method for inhibiting the replication or infectivity of a
virus comprising a contacting a virus or a virus-infected cell with
an effective amount of the compound of claim 24.
185. A method for inhibiting the replication or infectivity of a
virus comprising a contacting a virus or a virus-infected cell with
an effective amount of the compound of claim 25.
186. A method for inhibiting the replication or infectivity of a
virus comprising a contacting a virus or a virus-infected cell with
an effective amount of the compound of claim 26.
187. A method for inhibiting the replication or infectivity of a
virus comprising a contacting a virus or a virus-infected cell with
an effective amount of the compound of claim 27.
188. A method for inhibiting the replication or infectivity of a
virus comprising a contacting a virus or a virus-infected cell with
an effective amount of the compound of claim 28.
189. A method for inhibiting the replication or infectivity of a
virus comprising a contacting a virus or a virus-infected cell with
an effective amount of the compound of claim 29.
190. A method for inhibiting the replication or infectivity of a
virus comprising a contacting a virus or a virus-infected cell with
an effective amount of the compound of claim 30.
191. A method for inhibiting the replication or infectivity of a
virus comprising a contacting a virus or a virus-infected cell with
an effective amount of the compound of claim 3 1.
192. A method for inhibiting the replication or infectivity of a
virus comprising a contacting a virus or a virus-infected cell with
an effective amount of the compound of claim 32.
193. A method for inhibiting the replication or infectivity of a
virus comprising a contacting a virus or a virus-infected cell with
an effective amount of the compound of claim 33.
194. A method for inhibiting the replication or infectivity of a
virus comprising a contacting a virus or a virus-infected cell with
an effective amount of the compound of claim 34.
195. A method for inhibiting the replication or infectivity of a
virus comprising a contacting a virus or a virus-infected cell with
an effective amount of the compound of claim 35.
196. A method for inhibiting the replication or infectivity of a
virus comprising a contacting a virus or a virus-infected cell with
an effective amount of the compound of claim 36.
197. A method for inhibiting the replication or infectivity of a
virus comprising a contacting a virus or a virus-infected cell with
an effective amount of the compound of claim 37.
198. A method for inhibiting the replication or infectivity of a
virus comprising a contacting a virus or a virus-infected cell with
an effective amount of the compound of claim 38.
199. A method for inhibiting the replication or infectivity of a
virus comprising a contacting a virus or a virus-infected cell with
an effective amount of the compound of claim 39.
200. A method for inhibiting the replication or infectivity of a
virus comprising a contacting a virus or a virus-infected cell with
an effective amount of the compound of claim 40.
201. A method for causing immunosuppression in a patient comprising
administering to a patient in need thereof an effective amount of
the compound of claim 1.
202. A method for causing immunosuppression in a patient comprising
administering to a patient in need thereof an effective amount of
the compound of claim 2.
203. A method for causing immunosuppression in a patient comprising
administering to a patient in need thereof an effective amount of
the compound of claim 3.
204. A method for causing immunosuppression in a patient comprising
administering to a patient in need thereof an effective amount of
the compound of claim 4.
205. A method for causing immunosuppression in a patient comprising
administering to a patient in need thereof an effective amount of
the compound of claim 5.
206. A method for causing immunosuppression in a patient comprising
administering to a patient in need thereof an effective amount of
the compound of claim 6.
207. A method for causing immunosuppression in a patient comprising
administering to a patient in need thereof an effective amount of
the compound of claim 7.
208. A method for causing immunosuppression in a patient comprising
administering to a patient in need thereof an effective amount of
the compound of claim 8.
209. A method for causing immunosuppression in a patient comprising
administering to a patient in need thereof an effective amount of
the compound of claim 9.
210. A method for causing immunosuppression in a patient comprising
administering to a patient in need thereof an effective amount of
the compound of claim 10.
211. A method for causing immunosuppression in a patient comprising
administering to a patient in need thereof an effective amount of
the compound of claim 11.
212. A method for causing immunosuppression in a patient comprising
administering to a patient in need thereof an effective amount of
the compound of claim 12.
213. A method for causing immunosuppression in a patient comprising
administering to a patient in need thereof an effective amount of
the compound of claim 13.
214. A method for causing immunosuppression in a patient comprising
administering to a patient in need thereof an effective amount of
the compound of claim 14.
215. A method for causing immunosuppression in a patient comprising
administering to a patient in need thereof an effective amount of
the compound of claim 15.
216. A method for causing immunosuppression in a patient comprising
administering to a patient in need thereof an effective amount of
the compound of claim 16.
217. A method for causing immunosuppression in a patient comprising
administering to a patient in need thereof an effective amount of
the compound of claim 17.
218. A method for causing immunosuppression in a patient comprising
administering to a patient in need thereof an effective amount of
the compound of claim 18.
219. A method for causing immunosuppression in a patient comprising
administering to a patient in need thereof an effective amount of
the compound of claim 19.
220. A method for causing immunosuppression in a patient comprising
administering to a patient in need thereof an effective amount of
the compound of claim 20.
221. A method for causing immunosuppression in a patient comprising
administering to a patient in need thereof an effective amount of
the compound of claim 21.
222. A method for causing immunosuppression in a patient comprising
administering to a patient in need thereof an effective amount of
the compound of claim 22.
223. A method for causing immunosuppression in a patient comprising
administering to a patient in need thereof an effective amount of
the compound of claim 23.
224. A method for causing immunosuppression in a patient comprising
administering to a patient in need thereof an effective amount of
the compound of claim 24.
225. A method for causing immunosuppression in a patient comprising
administering to a patient in need thereof an effective amount of
the compound of claim 25.
226. A method for causing immunosuppression in a patient comprising
administering to a patient in need thereof an effective amount of
the compound of claim 26.
227. A method for causing immunosuppression in a patient comprising
administering to a patient in need thereof an effective amount of
the compound of claim 27.
228. A method for causing immunosuppression in a patient comprising
administering to a patient in need thereof an effective amount of
the compound of claim 28.
229. A method for causing immunosuppression in a patient comprising
administering to a patient in need thereof an effective amount of
the compound of claim 29.
230. A method for causing immunosuppression in a patient comprising
administering to a patient in need thereof an effective amount of
the compound of claim 30.
231. A method for causing immunosuppression in a patient comprising
administering to a patient in need thereof an effective amount of
the compound of claim 31.
232. A method for causing immunosuppression in a patient comprising
administering to a patient in need thereof an effective amount of
the compound of claim 32.
233. A method for causing immunosuppression in a patient comprising
administering to a patient in need thereof an effective amount of
the compound of claim 33.
234. A method for causing immunosuppression in a patient comprising
administering to a patient in need thereof an effective amount of
the compound of claim 34.
235. A method for causing immunosuppression in a patient comprising
administering to a patient in need thereof an effective amount of
the compound of claim 35.
236. A method for causing immunosuppression in a patient comprising
administering to a patient in need thereof an effective amount of
the compound of claim 36.
237. A method for causing immunosuppression in a patient comprising
administering to a patient in need thereof an effective amount of
the compound of claim 37.
238. A method for causing immunosuppression in a patient comprising
administering to a patient in need thereof an effective amount of
the compound of claim 38.
239. A method for causing immunosuppression in a patient comprising
administering to a patient in need thereof an effective amount of
the compound of claim 39.
240. A method for causing immunosuppression in a patient comprising
administering to a patient in need thereof an effective amount of
the compound of claim 40.
241. A method for treating or preventing an autoimmune disease in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 1.
242. A method for treating or preventing an autoimmune disease in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 2.
243. A method for treating or preventing an autoimmune disease in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 3.
244. A method for treating or preventing an autoimmune disease in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 4.
245. A method for treating or preventing an autoimmune disease in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 5.
246. A method for treating or preventing an autoimmune disease in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 6.
247. A method for treating or preventing an autoimmune disease in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 7.
248. A method for treating or preventing an autoimmune disease in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 8.
249. A method for treating or preventing an autoimmune disease in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 9.
250. A method for treating or preventing an autoimmune disease in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 10.
251. A method for treating or preventing an autoimmune disease in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 11.
252. A method for treating or preventing an autoimmune disease in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 12.
253. A method for treating or preventing an autoimmune disease in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 13.
254. A method for treating or preventing an autoimmune disease in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 14.
255. A method for treating or preventing an autoimmune disease in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 15.
256. A method for treating or preventing an autoimmune disease in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 16.
257. A method for treating or preventing an autoimmune disease in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 17.
258. A method for treating or preventing an autoimmune disease in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 18.
259. A method for treating or preventing an autoimmune disease in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 19.
260. A method for treating or preventing an autoimmune disease in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 20.
261. A method for treating or preventing an autoimmune disease in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 21.
262. A method for treating or preventing an autoimmune disease in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 22.
263. A method for treating or preventing an autoimmune disease in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 23.
264. A method for treating or preventing an autoimmune disease in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 24.
265. A method for treating or preventing an autoimmune disease in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 25.
266. A method for treating or preventing an autoimmune disease in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 26.
267. A method for treating or preventing an autoimmune disease in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 27.
268. A method for treating or preventing an autoimmune disease in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 28.
269. A method for treating or preventing an autoimmune disease in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 29.
270. A method for treating or preventing an autoimmune disease in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 30.
271. A method for treating or preventing an autoimmune disease in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 31.
272. A method for treating or preventing an autoimmune disease in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 32.
273. A method for treating or preventing an autoimmune disease in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 33.
274. A method for treating or preventing an autoimmune disease in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 34.
275. A method for treating or preventing an autoimmune disease in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 35.
276. A method for treating or preventing an autoimmune disease in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 36.
277. A method for treating or preventing an autoimmune disease in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 37.
278. A method for treating or preventing an autoimmune disease in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 38.
279. A method for treating or preventing an autoimmune disease in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 39.
280. A method for treating or preventing an autoimmune disease in a
patient comprising administering to a patient in need of such
treatment or prevention an effective amount of the compound of
claim 40.
281. The method of claim 241, wherein the autoimmune disease is
rheumatoid arthritis, insulin-dependent diabetes mellitus,
hemolytic anemia, rheumatic fever, thyroiditis, ulceractive
colitis, myesthethia gravis, glomerulonephritis, allergic
encephalomyelitis, continuing nerve and liver destruction following
viral hepatitis, multiple sclerosis, systemic lupus erythematosus,
juvenile diabetes, autoimmune haemolytic anaemia, psoriasis,
idiopathic thrombocytopenic purpura, active chronic hepatitis,
idiopathic leucopenia, primary biliary cirrhosis, thyrotoxicosis,
dermatomyositis, discoid lupus erythematosus, psoriatic arthritis,
regional enteritis, nephrotic syndrome, lupus nephritis, lupoid
hepatitis, Sjogren's syndrome, Goodpasture's syndrome, Wegener's
granulomatosis, scleroderma, Sezary's disease, uveitis, or mumps
orchitis.
282. The method of claim 242, wherein the autoimmune disease is
rheumatoid arthritis, insulin-dependent diabetes mellitus,
hemolytic anemia, rheumatic fever, thyroiditis, ulceractive
colitis, myesthethia gravis, glomerulonephritis, allergic
encephalomyelitis, continuing nerve and liver destruction following
viral hepatitis, multiple sclerosis, systemic lupus erythematosus,
juvenile diabetes, autoimmune haemolytic anaemia, psoriasis,
idiopathic thrombocytopenic purpura, active chronic hepatitis,
idiopathic leucopenia, primary biliary cirrhosis, thyrotoxicosis,
dermatomyositis, discoid lupus erythematosus, psoriatic arthritis,
regional enteritis, nephrotic syndrome, lupus nephritis, lupoid
hepatitis, Sjogren's syndrome, Goodpasture's syndrome, Wegener's
granulomatosis, scleroderma, Sezary's disease, uveitis, or mumps
orchitis.
283. The method of claim 243, wherein the autoimmune disease is
rheumatoid arthritis, insulin-dependent diabetes mellitus,
hemolytic anemia, rheumatic fever, thyroiditis, ulceractive
colitis, myesthethia gravis, glomerulonephritis, allergic
encephalomyelitis, continuing nerve and liver destruction following
viral hepatitis, multiple sclerosis, systemic lupus erythematosus,
juvenile diabetes, autoimmune haemolytic anaemia, psoriasis,
idiopathic thrombocytopenic purpura, active chronic hepatitis,
idiopathic leucopenia, primary biliary cirrhosis, thyrotoxicosis,
dermatomyositis, discoid lupus erythematosus, psoriatic arthritis,
regional enteritis, nephrotic syndrome, lupus nephritis, lupoid
hepatitis, Sjogren's syndrome, Goodpasture's syndrome, Wegener's
granulomatosis, scleroderma, Sezary's disease, uveitis, or mumps
orchitis.
284. The method of claim 244, wherein the autoimmune disease is
rheumatoid arthritis, insulin-dependent diabetes mellitus,
hemolytic anemia, rheumatic fever, thyroiditis, ulceractive
colitis, myesthethia gravis, glomerulonephritis, allergic
encephalomyelitis, continuing nerve and liver destruction following
viral hepatitis, multiple sclerosis, systemic lupus erythematosus,
juvenile diabetes, autoimmune haemolytic anaemia, psoriasis,
idiopathic thrombocytopenic purpura, active chronic hepatitis,
idiopathic leucopenia, primary biliary cirrhosis, thyrotoxicosis,
dermatomyositis, discoid lupus erythematosus, psoriatic arthritis,
regional enteritis, nephrotic syndrome, lupus nephritis, lupoid
hepatitis, Sjogren's syndrome, Goodpasture's syndrome, Wegener's
granulomatosis, scleroderma, Sezary's disease, uveitis, or mumps
orchitis.
285. The method of claim 245, wherein the autoimmune disease is
rheumatoid arthritis, insulin-dependent diabetes mellitus,
hemolytic anemia, rheumatic fever, thyroiditis, ulceractive
colitis, myesthethia gravis, glomerulonephritis, allergic
encephalomyelitis, continuing nerve and liver destruction following
viral hepatitis, multiple sclerosis, systemic lupus erythematosus,
juvenile diabetes, autoimmune haemolytic anaemia, psoriasis,
idiopathic thrombocytopenic purpura, active chronic hepatitis,
idiopathic leucopenia, primary biliary cirrhosis, thyrotoxicosis,
dermatomyositis, discoid lupus erythematosus, psoriatic arthritis,
regional enteritis, nephrotic syndrome, lupus nephritis, lupoid
hepatitis, Sjogren's syndrome, Goodpasture's syndrome, Wegener's
granulomatosis, scleroderma, Sezary's disease, uveitis, or mumps
orchitis.
286. The method of claim 246, wherein the autoimmune disease is
rheumatoid arthritis, insulin-dependent diabetes mellitus,
hemolytic anemia, rheumatic fever, thyroiditis, ulceractive
colitis, myesthethia gravis, glomerulonephritis, allergic
encephalomyelitis, continuing nerve and liver destruction following
viral hepatitis, multiple sclerosis, systemic lupus erythematosus,
juvenile diabetes, autoimmune haemolytic anaemia, psoriasis,
idiopathic thrombocytopenic purpura, active chronic hepatitis,
idiopathic leucopenia, primary biliary cirrhosis, thyrotoxicosis,
dermatomyositis, discoid lupus erythematosus, psoriatic arthritis,
regional enteritis, nephrotic syndrome, lupus nephritis, lupoid
hepatitis, Sjogren's syndrome, Goodpasture's syndrome, Wegener's
granulomatosis, scleroderma, Sezary's disease, uveitis, or mumps
orchitis.
287. The method of claim 247, wherein the autoimmune disease is
rheumatoid arthritis, insulin-dependent diabetes mellitus,
hemolytic anemia, rheumatic fever, thyroiditis, ulceractive
colitis, myesthethia gravis, glomerulonephritis, allergic
encephalomyelitis, continuing nerve and liver destruction following
viral hepatitis, multiple sclerosis, systemic lupus erythematosus,
juvenile diabetes, autoimmune haemolytic anaemia, psoriasis,
idiopathic thrombocytopenic purpura, active chronic hepatitis,
idiopathic leucopenia, primary biliary cirrhosis, thyrotoxicosis,
dermatomyositis, discoid lupus erythematosus, psoriatic arthritis,
regional enteritis, nephrotic syndrome, lupus nephritis, lupoid
hepatitis, Sjogren's syndrome, Goodpasture's syndrome, Wegener's
granulomatosis, scleroderma, Sezary's disease, uveitis, or mumps
orchitis.
288. The method of claim 248, wherein the autoimmune disease is
rheumatoid arthritis, insulin-dependent diabetes mellitus,
hemolytic anemia, rheumatic fever, thyroiditis, ulceractive
colitis, myesthethia gravis, glomerulonephritis, allergic
encephalomyelitis, continuing nerve and liver destruction following
viral hepatitis, multiple sclerosis, systemic lupus erythematosus,
juvenile diabetes, autoimmune haemolytic anaemia, psoriasis,
idiopathic thrombocytopenic purpura, active chronic hepatitis,
idiopathic leucopenia, primary biliary cirrhosis, thyrotoxicosis,
dermatomyositis, discoid lupus erythematosus, psoriatic arthritis,
regional enteritis, nephrotic syndrome, lupus nephritis, lupoid
hepatitis, Sjogren's syndrome, Goodpasture's syndrome, Wegener's
granulomatosis, scleroderma, Sezary's disease, uveitis, or mumps
orchitis.
289. The method of claim 249, wherein the autoimmune disease is
rheumatoid arthritis, insulin-dependent diabetes mellitus,
hemolytic anemia, rheumatic fever, thyroiditis, ulceractive
colitis, myesthethia gravis, glomerulonephritis, allergic
encephalomyelitis, continuing nerve and liver destruction following
viral hepatitis, multiple sclerosis, systemic lupus erythematosus,
juvenile diabetes, autoimmune haemolytic anaemia, psoriasis,
idiopathic thrombocytopenic purpura, active chronic hepatitis,
idiopathic leucopenia, primary biliary cirrhosis, thyrotoxicosis,
dermatomyositis, discoid lupus erythematosus, psoriatic arthritis,
regional enteritis, nephrotic syndrome, lupus nephritis, lupoid
hepatitis, Sjogren's syndrome, Goodpasture's syndrome, Wegener's
granulomatosis, scleroderma, Sezary's disease, uveitis, or mumps
orchitis.
290. The method of claim 250, wherein the autoimmune disease is
rheumatoid arthritis, insulin-dependent diabetes mellitus,
hemolytic anemia, rheumatic fever, thyroiditis, ulceractive
colitis, myesthethia gravis, glomerulonephritis, allergic
encephalomyelitis, continuing nerve and liver destruction following
viral hepatitis, multiple sclerosis, systemic lupus erythematosus,
juvenile diabetes, autoimmune haemolytic anaemia, psoriasis,
idiopathic thrombocytopenic purpura, active chronic hepatitis,
idiopathic leucopenia, primary biliary cirrhosis, thyrotoxicosis,
dermatomyositis, discoid lupus erythematosus, psoriatic arthritis,
regional enteritis, nephrotic syndrome, lupus nephritis, lupoid
hepatitis, Sjogren's syndrome, Goodpasture's syndrome, Wegener's
granulomatosis, scleroderma, Sezary's disease, uveitis, or mumps
orchitis.
291. The method of claim 251, wherein the autoimmune disease is
rheumatoid arthritis, insulin-dependent diabetes mellitus,
hemolytic anemia, rheumatic fever, thyroiditis, ulceractive
colitis, myesthethia gravis, glomerulonephritis, allergic
encephalomyelitis, continuing nerve and liver destruction following
viral hepatitis, multiple sclerosis, systemic lupus erythematosus,
juvenile diabetes, autoimmune haemolytic anaemia, psoriasis,
idiopathic thrombocytopenic purpura, active chronic hepatitis,
idiopathic leucopenia, primary biliary cirrhosis, thyrotoxicosis,
dermatomyositis, discoid lupus erythematosus, psoriatic arthritis,
regional enteritis, nephrotic syndrome, lupus nephritis, lupoid
hepatitis, Sjogren's syndrome, Goodpasture's syndrome, Wegener's
granulomatosis, scleroderma, Sezary's disease, uveitis, or mumps
orchitis.
292. The method of claim 252, wherein the autoimmune disease is
rheumatoid arthritis, insulin-dependent diabetes mellitus,
hemolytic anemia, rheumatic fever, thyroiditis, ulceractive
colitis, myesthethia gravis, glomerulonephritis, allergic
encephalomyelitis, continuing nerve and liver destruction following
viral hepatitis, multiple sclerosis, systemic lupus erythematosus,
juvenile diabetes, autoimmune haemolytic anaemia, psoriasis,
idiopathic thrombocytopenic purpura, active chronic hepatitis,
idiopathic leucopenia, primary biliary cirrhosis, thyrotoxicosis,
dermatomyositis, discoid lupus erythematosus, psoriatic arthritis,
regional enteritis, nephrotic syndrome, lupus nephritis, lupoid
hepatitis, Sjogren's syndrome, Goodpasture's syndrome, Wegener's
granulomatosis, scleroderma, Sezary's disease, uveitis, or mumps
orchitis.
293. The method of claim 253, wherein the autoimmune disease is
rheumatoid arthritis, insulin-dependent diabetes mellitus,
hemolytic anemia, rheumatic fever, thyroiditis, ulceractive
colitis, myesthethia gravis, glomerulonephritis, allergic
encephalomyelitis, continuing nerve and liver destruction following
viral hepatitis, multiple sclerosis, systemic lupus erythematosus,
juvenile diabetes, autoimmune haemolytic anaemia, psoriasis,
idiopathic thrombocytopenic purpura, active chronic hepatitis,
idiopathic leucopenia, primary biliary cirrhosis, thyrotoxicosis,
dermatomyositis, discoid lupus erythematosus, psoriatic arthritis,
regional enteritis, nephrotic syndrome, lupus nephritis, lupoid
hepatitis, Sjogren's syndrome, Goodpasture's syndrome, Wegener's
granulomatosis, scleroderma, Sezary's disease, uveitis, or mumps
orchitis.
294. The method of claim 254, wherein the autoimmune disease is
rheumatoid arthritis, insulin-dependent diabetes mellitus,
hemolytic anemia, rheumatic fever, thyroiditis, ulceractive
colitis, myesthethia gravis, glomerulonephritis, allergic
encephalomyelitis, continuing nerve and liver destruction following
viral hepatitis, multiple sclerosis, systemic lupus erythematosus,
juvenile diabetes, autoimmune haemolytic anaemia, psoriasis,
idiopathic thrombocytopenic purpura, active chronic hepatitis,
idiopathic leucopenia, primary biliary cirrhosis, thyrotoxicosis,
dermatomyositis, discoid lupus erythematosus, psoriatic arthritis,
regional enteritis, nephrotic syndrome, lupus nephritis, lupoid
hepatitis, Sjogren's syndrome, Goodpasture's syndrome, Wegener's
granulomatosis, scleroderma, Sezary's disease, uveitis, or mumps
orchitis.
295. The method of claim 255, wherein the autoimmune disease is
rheumatoid arthritis, insulin-dependent diabetes mellitus,
hemolytic anemia, rheumatic fever, thyroiditis, ulceractive
colitis, myesthethia gravis, glomerulonephritis, allergic
encephalomyelitis, continuing nerve and liver destruction following
viral hepatitis, multiple sclerosis, systemic lupus erythematosus,
juvenile diabetes, autoimmune haemolytic anaemia, psoriasis,
idiopathic thrombocytopenic purpura, active chronic hepatitis,
idiopathic leucopenia, primary biliary cirrhosis, thyrotoxicosis,
dermatomyositis, discoid lupus erythematosus, psoriatic arthritis,
regional enteritis, nephrotic syndrome, lupus nephritis, lupoid
hepatitis, Sjogren's syndrome, Goodpasture's syndrome, Wegener's
granulomatosis, scleroderma, Sezary's disease, uveitis, or mumps
orchitis.
296. The method of claim 256, wherein the autoimmune disease is
rheumatoid arthritis, insulin-dependent diabetes mellitus,
hemolytic anemia, rheumatic fever, thyroiditis, ulceractive
colitis, myesthethia gravis, glomerulonephritis, allergic
encephalomyelitis, continuing nerve and liver destruction following
viral hepatitis, multiple sclerosis, systemic lupus erythematosus,
juvenile diabetes, autoimmune haemolytic anaemia, psoriasis,
idiopathic thrombocytopenic purpura, active chronic hepatitis,
idiopathic leucopenia, primary biliary cirrhosis, thyrotoxicosis,
dermatomyositis, discoid lupus erythematosus, psoriatic arthritis,
regional enteritis, nephrotic syndrome, lupus nephritis, lupoid
hepatitis, Sjogren's syndrome, Goodpasture's syndrome, Wegener's
granulomatosis, scleroderma, Sezary's disease, uveitis, or mumps
orchitis.
297. The method of claim 257, wherein the autoimmune disease is
rheumatoid arthritis, insulin-dependent diabetes mellitus,
hemolytic anemia, rheumatic fever, thyroiditis, ulceractive
colitis, myesthethia gravis, glomerulonephritis, allergic
encephalomyelitis, continuing nerve and liver destruction following
viral hepatitis, multiple sclerosis, systemic lupus erythematosus,
juvenile diabetes, autoimmune haemolytic anaemia, psoriasis,
idiopathic thrombocytopenic purpura, active chronic hepatitis,
idiopathic leucopenia, primary biliary cirrhosis, thyrotoxicosis,
dermatomyositis, discoid lupus erythematosus, psoriatic arthritis,
regional enteritis, nephrotic syndrome, lupus nephritis, lupoid
hepatitis, Sjogren's syndrome, Goodpasture's syndrome, Wegener's
granulomatosis, scleroderma, Sezary's disease, uveitis, or mumps
orchitis.
298. The method of claim 258, wherein the autoimmune disease is
rheumatoid arthritis, insulin-dependent diabetes mellitus,
hemolytic anemia, rheumatic fever, thyroiditis, ulceractive
colitis, myesthethia gravis, glomerulonephritis, allergic
encephalomyelitis, continuing nerve and liver destruction following
viral hepatitis, multiple sclerosis, systemic lupus erythematosus,
juvenile diabetes, autoimmune haemolytic anaemia, psoriasis,
idiopathic thrombocytopenic purpura, active chronic hepatitis,
idiopathic leucopenia, primary biliary cirrhosis, thyrotoxicosis,
dermatomyositis, discoid lupus erythematosus, psoriatic arthritis,
regional enteritis, nephrotic syndrome, lupus nephritis, lupoid
hepatitis, Sjogren's syndrome, Goodpasture's syndrome, Wegener's
granulomatosis, scleroderma, Sezary's disease, uveitis, or mumps
orchitis.
299. The method of claim 259, wherein the autoimmune disease is
rheumatoid arthritis, insulin-dependent diabetes mellitus,
hemolytic anemia, rheumatic fever, thyroiditis, ulceractive
colitis, myesthethia gravis, glomerulonephritis, allergic
encephalomyelitis, continuing nerve and liver destruction following
viral hepatitis, multiple sclerosis, systemic lupus erythematosus,
juvenile diabetes, autoimmune haemolytic anaemia, psoriasis,
idiopathic thrombocytopenic purpura, active chronic hepatitis,
idiopathic leucopenia, primary biliary cirrhosis, thyrotoxicosis,
dermatomyositis, discoid lupus erythematosus, psoriatic arthritis,
regional enteritis, nephrotic syndrome, lupus nephritis, lupoid
hepatitis, Sjogren's syndrome, Goodpasture's syndrome, Wegener's
granulomatosis, scleroderma, Sezary's disease, uveitis, or mumps
orchitis.
300. The method of claim 260, wherein the autoimmune disease is
rheumatoid arthritis, insulin-dependent diabetes mellitus,
hemolytic anemia, rheumatic fever, thyroiditis, ulceractive
colitis, myesthethia gravis, glomerulonephritis, allergic
encephalomyelitis, continuing nerve and liver destruction following
viral hepatitis, multiple sclerosis, systemic lupus erythematosus,
juvenile diabetes, autoinimune haemolytic anaemia, psoriasis,
idiopathic thrombocytopenic purpura, active chronic hepatitis,
idiopathic leucopenia, primary biliary cirrhosis, thyrotoxicosis,
dermatomyositis, discoid lupus erythematosus, psoriatic arthritis,
regional enteritis, nephrotic syndrome, lupus nephritis, lupoid
hepatitis, Sjogren's syndrome, Goodpasture's syndrome, Wegener's
granulomatosis, scleroderma, Sezary's disease, uveitis, or mumps
orchitis.
301. The method of claim 261, wherein the autoimmune disease is
rheumatoid arthritis, insulin-dependent diabetes mellitus,
hemolytic anemia, rheumatic fever, thyroiditis, ulceractive
colitis, myesthethia gravis, glomerulonephritis, allergic
encephalomyelitis, continuing nerve and liver destruction following
viral hepatitis, multiple sclerosis, systemic lupus erythematosus,
juvenile diabetes, autoimmune haemolytic anaemia, psoriasis,
idiopathic thrombocytopenic purpura, active chronic hepatitis,
idiopathic leucopenia, primary biliary cirrhosis, thyrotoxicosis,
dermatomyositis, discoid lupus erythematosus, psoriatic arthritis,
regional enteritis, nephrotic syndrome, lupus nephritis, lupoid
hepatitis, Sjogren's syndrome, Goodpasture's syndrome, Wegener's
granulomatosis, scleroderma, Sezary's disease, uveitis, or mumps
orchitis.
302. The method of claim 262, wherein the autoimmune disease is
rheumatoid arthritis, insulin-dependent diabetes mellitus,
hemolytic anemia, rheumatic fever, thyroiditis, ulceractive
colitis, myesthethia gravis, glomerulonephritis, allergic
encephalomyelitis, continuing nerve and liver destruction following
viral hepatitis, multiple sclerosis, systemic lupus erythematosus,
juvenile diabetes, autoimmune haemolytic anaemia, psoriasis,
idiopathic thrombocytopenic purpura, active chronic hepatitis,
idiopathic leucopenia, primary biliary cirrhosis, thyrotoxicosis,
dermatomyositis, discoid lupus erythematosus, psoriatic arthritis,
regional enteritis, nephrotic syndrome, lupus nephritis, lupoid
hepatitis, Sjogren's syndrome, Goodpasture's syndrome, Wegener's
granulomatosis, scleroderma, Sezary's disease, uveitis, or mumps
orchitis.
303. The method of claim 263, wherein the autoimmune disease is
rheumatoid arthritis, insulin-dependent diabetes mellitus,
hemolytic anemia, rheumatic fever, thyroiditis, ulceractive
colitis, myesthethia gravis, glomerulonephritis, allergic
encephalomyelitis, continuing nerve and liver destruction following
viral hepatitis, multiple sclerosis, systemic lupus erythematosus,
juvenile diabetes, autoimmune haemolytic anaemia, psoriasis,
idiopathic thrombocytopenic purpura, active chronic hepatitis,
idiopathic leucopenia, primary biliary cirrhosis, thyrotoxicosis,
dermatomyositis, discoid lupus erythematosus, psoriatic arthritis,
regional enteritis, nephrotic syndrome, lupus nephritis, lupoid
hepatitis, Sjogren's syndrome, Goodpasture's syndrome, Wegener's
granulomatosis, scleroderma, Sezary's disease, uveitis, or mumps
orchitis.
304. The method of claim 264, wherein the autoimmune disease is
rheumatoid arthritis, insulin-dependent diabetes mellitus,
hemolytic anemia, rheumatic fever, thyroiditis, ulceractive
colitis, myesthethia gravis, glomerulonephritis, allergic
encephalomyelitis, continuing nerve and liver destruction following
viral hepatitis, multiple sclerosis, systemic lupus erythematosus,
juvenile diabetes, autoimmune haemolytic anaemia, psoriasis,
idiopathic thrombocytopenic purpura, active chronic hepatitis,
idiopathic leucopenia, primary biliary cirrhosis, thyrotoxicosis,
dermatomyositis, discoid lupus erythematosus, psoriatic arthritis,
regional enteritis, nephrotic syndrome, lupus nephritis, lupoid
hepatitis, Sjogren's syndrome, Goodpasture's syndrome, Wegener's
granulomatosis, scleroderma, Sezary's disease, uveitis, or mumps
orchitis.
305. The method of claim 265, wherein the autoimmune disease is
rheumatoid arthritis, insulin-dependent diabetes mellitus,
hemolytic anemia, rheumatic fever, thyroiditis, ulceractive
colitis, myesthethia gravis, glomerulonephritis, allergic
encephalomyelitis, continuing nerve and liver destruction following
viral hepatitis, multiple sclerosis, systemic lupus erythematosus,
juvenile diabetes, autoimmune haemolytic anaemia, psoriasis,
idiopathic thrombocytopenic purpura, active chronic hepatitis,
idiopathic leucopenia, primary biliary cirrhosis, thyrotoxicosis,
dermatomyositis, discoid lupus erythematosus, psoriatic arthritis,
regional enteritis, nephrotic syndrome, lupus nephritis, lupoid
hepatitis, Sjogren's syndrome, Goodpasture's syndrome, Wegener's
granulomatosis, scleroderma, Sezary's disease, uveitis, or mumps
orchitis.
306. The method of claim 266, wherein the autoimmune disease is
rheumatoid arthritis, insulin-dependent diabetes mellitus,
hemolytic anemia, rheumatic fever, thyroiditis, ulceractive
colitis, myesthethia gravis, glomerulonephritis, allergic
encephalomyelitis, continuing nerve and liver destruction following
viral hepatitis, multiple sclerosis, systemic lupus erythematosus,
juvenile diabetes, autoimmune haemolytic anaemia, psoriasis,
idiopathic thrombocytopenic purpura, active chronic hepatitis,
idiopathic leucopenia, primary biliary cirrhosis, thyrotoxicosis,
dermatomyositis, discoid lupus erythematosus, psoriatic arthritis,
regional enteritis, nephrotic syndrome, lupus nephritis, lupoid
hepatitis, Sjogren's syndrome, Goodpasture's syndrome, Wegener's
granulomatosis, scleroderma, Sezary's disease, uveitis, or mumps
orchitis.
307. The method of claim 267, wherein the autoimmune disease is
rheumatoid arthritis, insulin-dependent diabetes mellitus,
hemolytic anemia, rheumatic fever, thyroiditis, ulceractive
colitis, myesthethia gravis, glomerulonephritis, allergic
encephalomyelitis, continuing nerve and liver destruction following
viral hepatitis, multiple sclerosis, systemic lupus erythematosus,
juvenile diabetes, autoimmune haemolytic anaemia, psoriasis,
idiopathic thrombocytopenic purpura, active chronic hepatitis,
idiopathic leucopenia, primary biliary cirrhosis, thyrotoxicosis,
dermatomyositis, discoid lupus erythematosus, psoriatic arthritis,
regional enteritis, nephrotic syndrome, lupus nephritis, lupoid
hepatitis, Sjogren's syndrome, Goodpasture's syndrome, Wegener's
granulomatosis, scleroderma, Sezary's disease, uveitis, or mumps
orchitis.
308. The method of claim 268, wherein the autoimmune disease is
rheumatoid arthritis, insulin-dependent diabetes mellitus,
hemolytic anemia, rheumatic fever, thyroiditis, ulceractive
colitis, myesthethia gravis, glomerulonephritis, allergic
encephalomyelitis, continuing nerve and liver destruction following
viral hepatitis, multiple sclerosis, systemic lupus erythematosus,
juvenile diabetes, autoimmune haemolytic anaemia, psoriasis,
idiopathic thrombocytopenic purpura, active chronic hepatitis,
idiopathic leucopenia, primary biliary cirrhosis, thyrotoxicosis,
dermatomyositis, discoid lupus erythematosus, psoriatic arthritis,
regional enteritis, nephrotic syndrome, lupus nephritis, lupoid
hepatitis, Sjogren's syndrome, Goodpasture's syndrome, Wegener's
granulomatosis, scleroderma, Sezary's disease, uveitis, or mumps
orchitis.
309. The method of claim 269, wherein the autoimmune disease is
rheumatoid arthritis, insulin-dependent diabetes mellitus,
hemolytic anemia, rheumatic fever, thyroiditis, ulceractive
colitis, myesthethia gravis, glomerulonephritis, allergic
encephalomyelitis, continuing nerve and liver destruction following
viral hepatitis, multiple sclerosis, systemic lupus erythematosus,
juvenile diabetes, autoimmune haemolytic anaemia, psoriasis,
idiopathic thrombocytopenic purpura, active chronic hepatitis,
idiopathic leucopenia, primary biliary cirrhosis, thyrotoxicosis,
dermatomyositis, discoid lupus erythematosus, psoriatic arthritis,
regional enteritis, nephrotic syndrome, lupus nephritis, lupoid
hepatitis, Sjogren's syndrome, Goodpasture's syndrome, Wegener's
granulomatosis, scleroderma, Sezary's disease, uveitis, or mumps
orchitis.
310. The method of claim 270, wherein the autoimmune disease is
rheumatoid arthritis, insulin-dependent diabetes mellitus,
hemolytic anemia, rheumatic fever, thyroiditis, ulceractive
colitis, myesthethia gravis, glomerulonephritis, allergic
encephalomyelitis, continuing nerve and liver destruction following
viral hepatitis, multiple sclerosis, systemic lupus erythematosus,
juvenile diabetes, autoimmune haemolytic anaemia, psoriasis,
idiopathic thrombocytopenic purpura, active chronic hepatitis,
idiopathic leucopenia, primary biliary cirrhosis, thyrotoxicosis,
dermatomyositis, discoid lupus erythematosus, psoriatic arthritis,
regional enteritis, nephrotic syndrome, lupus nephritis, lupoid
hepatitis, Sjogren's syndrome, Goodpasture's syndrome, Wegener's
granulomatosis, scleroderma, Sezary's disease, uveitis, or mumps
orchitis.
311. The method of claim 271, wherein the autoimmune disease is
rheumatoid arthritis, insulin-dependent diabetes mellitus,
hemolytic anemia, rheumatic fever, thyroiditis, ulceractive
colitis, myesthethia gravis, glomerulonephritis, allergic
encephalomyelitis, continuing nerve and liver destruction following
viral hepatitis, multiple sclerosis, systemic lupus erythematosus,
juvenile diabetes, autoimmune haemolytic anaemia, psoriasis,
idiopathic thrombocytopenic purpura, active chronic hepatitis,
idiopathic leucopenia, primary biliary cirrhosis, thyrotoxicosis,
dermatomyositis, discoid lupus erythematosus, psoriatic arthritis,
regional enteritis, nephrotic syndrome, lupus nephritis, lupoid
hepatitis, Sjogren's syndrome, Goodpasture's syndrome, Wegener's
granulomatosis, scleroderma, Sezary's disease, uveitis, or mumps
orchitis.
312. The method of claim 272, wherein the autoimmune disease is
rheumatoid arthritis, insulin-dependent diabetes mellitus,
hemolytic anemia, rheumatic fever, thyroiditis, ulceractive
colitis, myesthethia gravis, glomerulonephritis, allergic
encephalomyelitis, continuing nerve and liver destruction following
viral hepatitis, multiple sclerosis, systemic lupus erythematosus,
juvenile diabetes, autoimmune haemolytic anaemia, psoriasis,
idiopathic thrombocytopenic purpura, active chronic hepatitis,
idiopathic leucopenia, primary biliary cirrhosis, thyrotoxicosis,
dermatomyositis, discoid lupus erythematosus, psoriatic arthritis,
regional enteritis, nephrotic syndrome, lupus nephritis, lupoid
hepatitis, Sjogren's syndrome, Goodpasture's syndrome, Wegener's
granulomatosis, scleroderma, Sezary's disease, uveitis, or mumps
orchitis.
313. The method of claim 273, wherein the autoimmune disease is
rheumatoid arthritis, insulin-dependent diabetes mellitus,
hemolytic anemia, rheumatic fever, thyroiditis, ulceractive
colitis, myesthethia gravis, glomerulonephritis, allergic
encephalomyelitis, continuing nerve and liver destruction following
viral hepatitis, multiple sclerosis, systemic lupus erythematosus,
juvenile diabetes, autoimmune haemolytic anaemia, psoriasis,
idiopathic thrombocytopenic purpura, active chronic hepatitis,
idiopathic leucopenia, primary biliary cirrhosis, thyrotoxicosis,
dermatomyositis, discoid lupus erythematosus, psoriatic arthritis,
regional enteritis, nephrotic syndrome, lupus nephritis, lupoid
hepatitis, Sjogren's syndrome, Goodpasture's syndrome, Wegener's
granulomatosis, scleroderma, Sezary's disease, uveitis, or mumps
orchitis.
314. The method of claim 274, wherein the autoimmune disease is
rheumatoid arthritis, insulin-dependent diabetes mellitus,
hemolytic anemia, rheumatic fever, thyroiditis, ulceractive
colitis, myesthethia gravis, glomerulonephritis, allergic
encephalomyelitis, continuing nerve and liver destruction following
viral hepatitis, multiple sclerosis, systemic lupus erythematosus,
juvenile diabetes, autoimmune haemolytic anaemia, psoriasis,
idiopathic thrombocytopenic purpura, active chronic hepatitis,
idiopathic leucopenia, primary biliary cirrhosis, thyrotoxicosis,
dermatomyositis, discoid lupus erythematosus, psoriatic arthritis,
regional enteritis, nephrotic syndrome, lupus nephritis, lupoid
hepatitis, Sjogren's syndrome, Goodpasture's syndrome, Wegener's
granulomatosis, scleroderma, Sezary's disease, uveitis, or mumps
orchitis.
315. The method of claim 275, wherein the autoimmune disease is
rheumatoid arthritis, insulin-dependent diabetes mellitus,
hemolytic anemia, rheumatic fever, thyroiditis, ulceractive
colitis, myesthethia gravis, glomerulonephritis, allergic
encephalomyelitis, continuing nerve and liver destruction following
viral hepatitis, multiple sclerosis, systemic lupus erythematosus,
juvenile diabetes, autoimmune haemolytic anaemia, psoriasis,
idiopathic thrombocytopenic purpura, active chronic hepatitis,
idiopathic leucopenia, primary biliary cirrhosis, thyrotoxicosis,
dermatomyositis, discoid lupus erythematosus, psoriatic arthritis,
regional enteritis, nephrotic syndrome, lupus nephritis, lupoid
hepatitis, Sjogren's syndrome, Goodpasture's syndrome, Wegener's
granulomatosis, scleroderma, Sezary's disease, uveitis, or mumps
orchitis.
316. The method of claim 276, wherein the autoimmune disease is
rheumatoid arthritis, insulin-dependent diabetes mellitus,
hemolytic anemia, rheumatic fever, thyroiditis, ulceractive
colitis, myesthethia gravis, glomerulonephritis, allergic
encephalomyelitis, continuing nerve and liver destruction following
viral hepatitis, multiple sclerosis, systemic lupus erythematosus,
juvenile diabetes, autoimmune haemolytic anaemia, psoriasis,
idiopathic thrombocytopenic purpura, active chronic hepatitis,
idiopathic leucopenia, primary biliary cirrhosis, thyrotoxicosis,
dermatomyositis, discoid lupus erythematosus, psoriatic arthritis,
regional enteritis, nephrotic syndrome, lupus nephritis, lupoid
hepatitis, Sjogren's syndrome, Goodpasture's syndrome, Wegener's
granulomatosis, scleroderma, Sezary's disease, uveitis, or mumps
orchitis.
317. The method of claim 277, wherein the autoimmune disease is
rheumatoid arthritis, insulin-dependent diabetes mellitus,
hemolytic anemia, rheumatic fever, thyroiditis, ulceractive
colitis, myesthethia gravis, glomerulonephritis, allergic
encephalomyelitis, continuing nerve and liver destruction following
viral hepatitis, multiple sclerosis, systemic lupus erythematosus,
juvenile diabetes, autoimmune haemolytic anaemia, psoriasis,
idiopathic thrombocytopenic purpura, active chronic hepatitis,
idiopathic leucopenia, primary biliary cirrhosis, thyrotoxicosis,
dermatomyositis, discoid lupus erythematosus, psoriatic arthritis,
regional enteritis, nephrotic syndrome, lupus nephritis, lupoid
hepatitis, Sjogren's syndrome, Goodpasture's syndrome, Wegener's
granulomatosis, scleroderma, Sezary's disease, uveitis, or mumps
orchitis.
318. The method of claim 278, wherein the autoimmune disease is
rheumatoid arthritis, insulin-dependent diabetes mellitus,
hemolytic anemia, rheumatic fever, thyroiditis, ulceractive
colitis, myesthethia gravis, glomerulonephritis, allergic
encephalomyelitis, continuing nerve and liver destruction following
viral hepatitis, multiple sclerosis, systemic lupus erythematosus,
juvenile diabetes, autoimmune haemolytic anaemia, psoriasis,
idiopathic thrombocytopenic purpura, active chronic hepatitis,
idiopathic leucopenia, primary biliary cirrhosis, thyrotoxicosis,
dermatomyositis, discoid lupus erythematosus, psoriatic arthritis,
regional enteritis, nephrotic syndrome, lupus nephritis, lupoid
hepatitis, Sjogren's syndrome, Goodpasture's syndrome, Wegener's
granulomatosis, scleroderma, Sezary's disease, uveitis, or mumps
orchitis.
319. The method of claim 279, wherein the autoimmune disease is
rheumatoid arthritis, insulin-dependent diabetes mellitus,
hemolytic anemia, rheumatic fever, thyroiditis, ulceractive
colitis, myesthethia gravis, glomerulonephritis, allergic
encephalomyelitis, continuing nerve and liver destruction following
viral hepatitis, multiple sclerosis, systemic lupus erythematosus,
juvenile diabetes, autoimmune haemolytic anaemia, psoriasis,
idiopathic thrombocytopenic purpura, active chronic hepatitis,
idiopathic leucopenia, primary biliary cirrhosis, thyrotoxicosis,
dermatomyositis, discoid lupus erythematosus, psoriatic arthritis,
regional enteritis, nephrotic syndrome, lupus nephritis, lupoid
hepatitis, Sjogren's syndrome, Goodpasture's syndrome, Wegener's
granulomatosis, scleroderma, Sezary's disease, uveitis, or mumps
orchitis.
320. The method of claim 280, wherein the autoimmune disease is
rheumatoid arthritis, insulin-dependent diabetes mellitus,
hemolytic anemia, rheumatic fever, thyroiditis, ulceractive
colitis, myesthethia gravis, glomerulonephritis, allergic
encephalomyelitis, continuing nerve and liver destruction following
viral hepatitis, multiple sclerosis, systemic lupus erythematosus,
juvenile diabetes, autoimmune haemolytic anaemia, psoriasis,
idiopathic thrombocytopenic purpura, active chronic hepatitis,
idiopathic leucopenia, primary biliary cirrhosis, thyrotoxicosis,
dermatomyositis, discoid lupus erythematosus, psoriatic arthritis,
regional enteritis, nephrotic syndrome, lupus nephritis, lupoid
hepatitis, Sjogren's syndrome, Goodpasture's syndrome, Wegener's
granulomatosis, scleroderna, Sezary's disease, uveitis, or mumps
orchitis.
321. A pharmaceutical composition comprising the compound of claim
1 and a pharmaceutically acceptable carrier.
322. A pharmaceutical composition comprising the compound of claim
2 and a pharmaceutically acceptable carrier.
323. A pharmaceutical composition comprising the compound of claim
3 and a pharmaceutically acceptable carrier.
324. A pharmaceutical composition comprising the compound of claim
4 and a pharmaceutically acceptable carrier.
325. A pharmaceutical composition comprising the compound of claim
5 and a pharmaceutically acceptable carrier.
326. A pharmaceutical composition comprising the compound of claim
6 and a pharmaceutically acceptable carrier.
327. A pharmaceutical composition comprising the compound of claim
7 and a pharmaceutically acceptable carrier.
328. A pharmaceutical composition comprising the compound of claim
8 and a pharmaceutically acceptable carrier.
329. A pharmaceutical composition comprising the compound of claim
9 and a pharmaceutically acceptable carrier.
330. A pharmaceutical composition comprising the compound of claim
10 and a pharmaceutically acceptable carrier.
331. A pharmaceutical composition comprising the compound of claim
11 and a pharmaceutically acceptable carrier.
332. A pharmaceutical composition comprising the compound of claim
12 and a pharmaceutically acceptable carrier.
333. A pharmaceutical composition comprising the compound of claim
13 and a pharmaceutically acceptable carrier.
334. A pharmaceutical composition comprising the compound of claim
14 and a pharmaceutically acceptable carrier.
335. A pharmaceutical composition comprising the compound of claim
15 and a pharmaceutically acceptable carrier.
336. A pharmaceutical composition comprising the compound of claim
16 and a pharmaceutically acceptable carrier.
337. A pharmaceutical composition comprising the compound of claim
17 and a pharmaceutically acceptable carrier.
338. A pharmaceutical composition comprising the compound of claim
18 and a pharmaceutically acceptable carrier.
339. A pharmaceutical composition comprising the compound of claim
19 and a pharmaceutically acceptable carrier.
340. A pharmaceutical composition comprising the compound of claim
20 and a pharmaceutically acceptable carrier.
341. A pharmaceutical composition comprising the compound of claim
21 and a pharmaceutically acceptable carrier.
342. A pharmaceutical composition comprising the compound of claim
22 and a pharmaceutically acceptable carrier.
343. A pharmaceutical composition comprising the compound of claim
23 and a pharmaceutically acceptable carrier.
344. A pharmaceutical composition comprising the compound of claim
24 and a pharmaceutically acceptable carrier.
345. A pharmaceutical composition comprising the compound of claim
25 and a pharmaceutically acceptable carrier.
346. A pharmaceutical composition comprising the compound of claim
26 and a pharmaceutically acceptable carrier.
347. A pharmaceutical composition comprising the compound of claim
27 and a pharmaceutically acceptable carrier.
348. A pharmaceutical composition comprising the compound of claim
28 and a pharmaceutically acceptable carrier.
349. A pharmaceutical composition comprising the compound of claim
29 and a pharmaceutically acceptable carrier.
350. A pharmaceutical composition comprising the compound of claim
30 and a pharmaceutically acceptable carrier.
351. A pharmaceutical composition comprising the compound of claim
31 and a pharmaceutically acceptable carrier.
352. A pharmaceutical composition comprising the compound of claim
32 and a pharmaceutically acceptable carrier.
353. A pharmaceutical composition comprising the compound of claim
33 and a pharmaceutically acceptable carrier.
354. A pharmaceutical composition comprising the compound of claim
34 and a pharmaceutically acceptable carrier.
355. A pharmaceutical composition comprising the compound of claim
35 and a pharmaceutically acceptable carrier.
356. A pharmaceutical composition comprising the compound of claim
36 and a pharmaceutically acceptable carrier.
357. A pharmaceutical composition comprising the compound of claim
37 and a pharmaceutically acceptable carrier.
358. A pharmaceutical composition comprising the compound of claim
38 and a pharmaceutically acceptable carrier.
359. A pharmaceutical composition comprising the compound of claim
39 and a pharmaceutically acceptable carrier.
360. A pharmaceutical composition comprising the compound of claim
40 and a pharmaceutically acceptable carrier.
Description
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/305,870, filed Jul. 18, 2001, which is
incorporated by reference herein in its entirety.
1. FIELD OF THE INVENTION
[0002] The present invention relates to Pyrrole-Type compounds,
compositions comprising Pyrrole-Type compounds, and methods useful
for treating or preventing cancer or a neoplastic disorder
comprising administering a Pyrrole-Type compound. The compounds,
compositions, and methods of the invention are also useful for
inhibiting the growth of a cancer cell or neoplastic cell. The
present invention also relates to Pyrrole-Type compounds,
compositions, and methods useful for treating or preventing a viral
infection. The compounds, compositions, and methods of the
invention are also useful for inhibiting the replication or
infectivity of a virus. The present invention also relates to
Pyrrole-Type compounds, compositions, and methods useful for
causing immunosuppression. The compounds and methods are also
useful for treating or preventing an autoimmune disease.
2. BACKGROUND OF THE INVENTION
2.1. Cancer and Neoplastic Disease
[0003] Cancer affects approximately 20 million adults and children
worldwide, and this year, more than 9 million new cases will be
diagnosed (International Agency for Research on Cancer;
www.irac.fr). According to the American Cancer Society, about
563,100 Americans are expected to die of cancer this year, more
than 1500 people a day. Since 1990, in the United States alone,
nearly five million lives have been lost to cancer, and
approximately 12 million new cases have been diagnosed.
[0004] Currently, cancer therapy involves surgery, chemotherapy
and/or radiation treatment to eradicate neoplastic cells in a
patient (see, for example, Stockdale, 1998, "Principles of Cancer
Patient Management", in Scientific American: Medicine, vol. 3,
Rubenstein and Federman, eds., Chapter 12, Section IV). All of
these approaches pose significant drawbacks for the patient.
Surgery, for example, may be contraindicated due to the health of
the patient or may be unacceptable to the patient. Additionally,
surgery may not completely remove the neoplastic tissue. Radiation
therapy is effective only when the irradiated neoplastic tissue
exhibits a higher sensitivity to radiation than normal tissue, and
radiation therapy can also often elicit serious side effects. (Id.)
With respect to chemotherapy, there are a variety of
chemotherapeutic agents available for treatment of neoplastic
disease. However, despite the availability of a variety of
chemotherapeutic agents, chemotherapy has many drawbacks (see, for
example, Stockdale, 1998, "Principles Of Cancer Patient Management"
in Scientific American Medicine, vol. 3, Rubenstein and Federman,
eds., ch. 12, sect. 10). Almost all chemotherapeutic agents are
toxic, and chemotherapy causes significant, and often dangerous,
side effects, including severe nausea, bone marrow depression,
immunosuppression, etc. Additionally, many tumor cells are
resistant or develop resistance to chemotherapeutic agents through
multi-drug resistance.
[0005] Tamura et al., JP93086374, discloses metacycloprodigiosin
and/or prodigiosin-25C as being useful for treating leukemia, but
provides data for only prodigiosin-25C activity against L-5178Y
cells in vitro. Hirata et al., JP-10120562, discloses the use of
cycloprodigiosin as an inhibitor of the vacuolar ATPase proton pump
and states that cycloprodigiosin may have anti-tumor enhancing
activity. Hirata et al., JP-10120563 discloses the use of
cycloprodigiosin as a therapeutic drug for leukemia, as an
immunosuppressant, and as an apoptosis inducer. JP61034403, to
Kirin Brewery Co. Ltd, describes prodigiosin for increasing the
survival time of mice with leukemia. Boger, 1988, J. Org. Chem.
53:1405-1415 discloses in vitro cytotoxic activity of prodigiosin,
prodigiosene, and 2-methyl-3-pentylprodigiosene against mouse P388
leukemia cells. The National Cancer Institute,
http://dtp.nci.nih.gov, discloses data obtained from the results of
a human-tumor-cell-line screen, including screening of
butylcycloheptyl-prodiginine HCl; however, the screen provides no
indication that the compounds of the screen are selective for
cancer cells (e.g., as compared to normal cells).
[0006] Therefore, there is a significant need in the art for novel
compounds and compositions, and methods that are useful for
treating cancer or neoplastic disease with reduced or without the
aforementioned side effects. Further, there is a need for cancer
treatments that provide cancer-cell-specific therapies with
increased specificity and decreased toxicity.
2.2. Viruses and Disease
[0007] In addition to cancer, an enormous number of human and
animal diseases result from virulent and opportunistic viral
infections (see Belshe (Ed.) 1984 Textbook of Human Virology, PSG
Publishing, Littleton, Mass.). Viral diseases of a wide array of
tissues, including the respiratory tract, CNS, skin, genitourinary
tract, eyes, ears, immune system, gastrointestinal tract, and
musculoskeletal system, affect a vast number of humans of all ages
(see Table 328-2 In: Wyngaarden and Smith, 1988, Cecil Textbook of
Medicine, 18.sup.th Ed., W.B. Saunders Co., Philadelphia, pp.
1750-1753).
[0008] Although considerable effort has been invested in the design
of effective anti-viral therapies, viral infections continue to
threaten the lives of millions of people worldwide. In general,
attempts to develop anti-viral drugs have focused on several stages
of viral life cycle (See e.g., Mitsuya, H., et al., 1991, FASEB J.
5:2369-2381, discussing HIV). However, a common drawback associated
with using of many current anti-viral drugs is their deleterious
side effects, such as toxicity to the host or resistance by certain
viral strains.
[0009] Accordingly, there is a need in the art for anti-viral
compounds, compositions, and methods that allow for safe and
effective treatment of viral disease without the above-mentioned
disadvantages.
2.3. Immunosuppression
[0010] The immune system, when working properly, protects an
individual from infection and from growth of cancers. In order to
carry out these functions, however, the immune system must be able
to recognize and mount an attack against foreign antigens
(including cancer-specific antigens), but not against self antigens
that are present on normal cells throughout the body.
[0011] To improve its level of protection, it is possible to
stimulate the immune system. Vaccines, including single-protein
antigens such as diptheria toxoid, are widely used to generate
immunity against a specific antigen and thus a specific disease
associated with that antigen. Where general stimulation of the
immune system is desired, this type of stimulation can sometimes be
achieved using nonspecific agents such as adjuvants, interleukins,
interferons, and colony stimulating factors.
[0012] Occasionally, the immune system loses its critical ability
to distinguish self from non-self antigens. The resulting
immunological assault on the individual's own tissues can take the
form of autoimmune disease, for example, systemic lupus
erythrematosis, Type 1 diabetes, or rheumatoid arthritis. In such a
case, or alternatively where the individual is the recipient of a
transplanted organ or tissue, suppression rather than stimulation
of the immune response is desirable. Non-specific down-regulation
of the immune response is typically achieved by treatment with
corticosteroids, azathioprine, cyclosporine, tacrolimus (FK506),
rapamycin, or mycophenolate mofetil. Certain immunoglobulins,
including the monoclonal antibody OKT3, have also been used for
this purpose. Suppression of immunity against a specific antigen,
called "tolerance induction," may also be possible. Methods that
have been used for inducing tolerance against a particular antigen
include intravenous or repeated topical administration of the
antigen in dilute form, treatment with a very high dose of the
antigen, and oral administration of the antigen.
[0013] Presently used immunosupressive agents, such as Cyclosporin
A and steroids, are potent but can cause severe side effects in a
dose dependent manner.
[0014] Accordingly, there is a need for new safe compounds,
compositions, and methods that are useful for treating diseases
that are responsive to immunomodulation.
[0015] Citation or identification of any reference in Section 2 of
this application is not an admission that such reference is
available as prior art to the present invention.
3. SUMMARY OF THE INVENTION
Formula I
[0016] The present invention encompasses novel compounds having the
general Formula (I): 1
[0017] and pharmaceutically acceptable salts thereof, wherein:
[0018] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, and --C(O)OCH.sub.2C.sub.6H.sub.5;
and
[0019] n is an integer ranging from 1 and 5.
[0020] The compounds of Formula (I) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. The compounds of Formula (I) or a pharmaceutically
acceptable salt thereof are also useful for inhibiting the growth
of a cancer cell or neoplastic cell. The compounds of Formula (I)
or a pharmaceutically acceptable salt thereof are useful for
treating or preventing a viral infection in a patient in need of
such treatment or prevention. The compounds of Formula (I) or a
pharmaceutically acceptable salt thereof are also useful for
inhibiting the replication or infectivity of a virus. The compounds
of Formula (I) or a pharmaceutically acceptable salt thereof are
also useful for causing immunosuppression in a patient in need
thereof. The compounds of Formula (I) or a pharmaceutically
acceptable salt thereof are also useful for treating or preventing
an autoimmune disease in a patient in need of such treatment or
prevention.
[0021] The present invention provides compositions comprising a
pharmaceutically acceptable carrier and an effective amount of a
compound of Formula (I) or a pharmaceutically acceptable salt
thereof. The compositions comprising a pharmaceutically acceptable
carrier and a compound of Formula (I) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. These compositions are also useful for inhibiting
the growth of a cancer cell or neoplastic cell. The compositions
comprising a pharmaceutically acceptable carrier and a compound of
Formula (I) or a pharmaceutically acceptable salt thereof are also
useful for treating or preventing a viral infection in a patient in
need of such treatment or prevention. These compositions are also
useful for inhibiting the replication or infectivity of a virus.
The compositions comprising a pharmaceutically acceptable carrier
and a compound of Formula (I) or a pharmaceutically acceptable salt
thereof are also useful for causing immunosuppression in a patient
in need thereof. The compositions comprising a pharmaceutically
acceptable carrier and a compound of Formula (I) or a
pharmaceutically acceptable salt thereof are also useful for
treating or preventing an autoimmune disease in a patient in need
of such treatment or prevention.
[0022] The invention further provides methods for treating or
preventing cancer or neoplastic disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (I) or a
pharmaceutically acceptable salt thereof.
[0023] The invention further provides methods for inhibiting the
growth of a cancer cell or neoplastic cell comprising contacting a
cancer cell or neoplastic cell with an effective amount of a
compound having the general Formula (I) or a pharmaceutically
acceptable salt thereof.
[0024] The invention further provides methods for treating or
preventing a viral infection in a patient comprising administering
to a patient in need of such treatment or prevention an effective
amount of a compound of Formula (I) or a pharmaceutically
acceptable salt thereof.
[0025] The invention further provides methods for inhibiting the
replication or infectivity of a virus comprising contacting a virus
or a virus-infected cell with an effective amount of a compound
having the general Formula (I) or a pharmaceutically acceptable
salt thereof.
[0026] The invention further provides methods for causing
immunosuppression in a patient comprising administering to a
patient in need thereof an effective amount of a compound of
Formula (I) or a pharmaceutically acceptable salt thereof.
[0027] The invention further provides methods for treating or
preventing an autoimmune disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (I) or a
pharmaceutically acceptable salt thereof.
Formula II
[0028] The present invention still further provides novel compounds
having the general Formula (II): 2
[0029] and pharmaceutically acceptable salts thereof, wherein:
[0030] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, and --C(O)OCH.sub.2C.sub.6H.sub.5;
and
[0031] n is an integer ranging from 1 and 5.
[0032] The compounds of Formula (II) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. The compounds of Formula (II) or a pharmaceutically
acceptable salt thereof are also useful for inhibiting the growth
of a cancer cell or neoplastic cell. The compounds of Formula (II)
or a pharmaceutically acceptable salt thereof are useful for
treating or preventing a viral infection in a patient in need of
such treatment or prevention. The compounds of Formula (II) or a
pharmaceutically acceptable salt thereof are also useful for
inhibiting the replication or infectivity of a virus. The compounds
of Formula (II) or a pharmaceutically acceptable salt thereof are
also useful for causing immunosuppression in a patient in need
thereof. The compounds of Formula (II) or a pharmaceutically
acceptable salt thereof are also useful for treating or preventing
an autoimmune disorder in a patient in need of such treatment or
prevention.
[0033] The present invention provides compositions comprising a
pharmaceutically acceptable carrier and an effective amount of a
compound of Formula (II) or a pharmaceutically acceptable salt
thereof. The compositions comprising a pharmaceutically acceptable
carrier and a compound of Formula (II) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. These compositions are also useful for inhibiting
the growth of a cancer cell or neoplastic cell. The compositions
comprising a pharmaceutically acceptable carrier and a compound of
Formula (II) or a pharmaceutically acceptable salt thereof are also
useful for treating or preventing a viral infection in a patient in
need of such treatment or prevention. These compositions are also
useful for inhibiting the replication or infectivity of a virus.
The compositions comprising a pharmaceutically acceptable carrier
and a compound of Formula (II) or a pharmaceutically acceptable
salt thereof are also useful for causing immunosuppression in a
patient in need thereof. The compositions comprising a
pharmaceutically acceptable carrier and a compound of Formula (II)
or a pharmaceutically acceptable salt thereof are also useful for
treating or preventing an autoimmune disease in a patient in need
of such treatment or prevention.
[0034] The invention further provides methods for treating or
preventing cancer or neoplastic disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (II) or a
pharmaceutically acceptable salt thereof.
[0035] The invention further provides methods for inhibiting the
growth of a cancer cell or neoplastic cell comprising contacting a
cancer cell or neoplastic cell with an effective amount of a
compound having the general Formula (II) or a pharmaceutically
acceptable salt thereof.
[0036] The invention further provides methods for treating or
preventing a viral infection in a patient comprising administering
to a patient in need of such treatment or prevention an effective
amount of a compound of Formula (II) or a pharmaceutically
acceptable salt thereof.
[0037] The invention further provides methods for inhibiting the
replication or infectivity of a virus comprising contacting a virus
or a virus-infected cell with an effective amount of a compound
having the general Formula (II) or a pharmaceutically acceptable
salt thereof.
[0038] The invention further provides methods for causing
immunosuppression in a patient comprising administering to a
patient in need thereof an effective amount of a compound of
Formula (II) or a pharmaceutically acceptable salt thereof.
[0039] The invention further provides methods for treating or
preventing an autoimmune disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (II) or a
pharmaceutically acceptable salt thereof.
Formula III
[0040] The present invention still further provides novel compounds
having the general Formula (III): 3
[0041] and pharmaceutically acceptable salts thereof, wherein:
[0042] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, and --C(O)OCH.sub.2C.sub.6H.sub.5;
[0043] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5, the --CH.sub.2C.sub.6H.sub.5 being
unsubstituted or substituted on the phenyl with one or more
methoxyl, halogen, methyl, nitro, trifluoromethyl, or
methoxylcarbonyl groups;
[0044] R.sub.3 is --CH.sub.3, --CH.sub.2CH.sub.3, or
--C.sub.6H.sub.5;
[0045] R.sub.4 is --H, a C.sub.1-C.sub.15 straight chain alkyl,
-2-pyrrolyl, -3-pyrrolyl, -2-furanyl, -3-furanyl, or
--C.sub.6H.sub.5, the --C.sub.6H.sub.5 being unsubstituted or
substituted with one or more methyl, methoxyl, halogen,
trifluoromethyl, or methoxycarbonyl groups;
[0046] R.sub.5 is --H, a C.sub.1-C.sub.12 straight chain alkyl,
i-C.sub.3H.sub.7, or --C.sub.6H.sub.5;
[0047] R.sub.6 is --H, a C.sub.1-C.sub.12 straight chain alkyl,
i-C.sub.3H.sub.7, C.sub.3-C.sub.7 cycloalkyl, or
--C.sub.6H.sub.5.
[0048] The compounds of Formula (III) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. The compounds of Formula (III) or a pharmaceutically
acceptable salt thereof are also useful for inhibiting the growth
of a cancer cell or neoplastic cell. The compounds of Formula (III)
or a pharmaceutically acceptable salt thereof are useful for
treating or preventing a viral infection in a patient in need of
such treatment or prevention. The compounds of Formula (III) or a
pharmaceutically acceptable salt thereof are also useful for
inhibiting the replication or infectivity of a virus. The compounds
of Formula (III) or a pharmaceutically acceptable salt thereof are
also useful for causing immunosuppression in a patient in need
thereof. The compounds of Formula (III) or a pharmaceutically
acceptable salt thereof are also useful for treating or preventing
an autoimmune disorder in a patient in need of such treatment or
prevention.
[0049] The present invention provides compositions comprising a
pharmaceutically acceptable carrier and an effective amount of a
compound of Formula (III) or a pharmaceutically acceptable salt
thereof. The compositions comprising a pharmaceutically acceptable
carrier and a compound of Formula (III) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. These compositions are also useful for inhibiting
the growth of a cancer cell or neoplastic cell. The compositions
comprising a pharmaceutically acceptable carrier and a compound of
Formula (III) or a pharmaceutically acceptable salt thereof are
also useful for treating or preventing a viral infection in a
patient in need of such treatment or prevention. These compositions
are also useful for inhibiting the replication or infectivity of a
virus. The compositions comprising a pharmaceutically acceptable
carrier and a compound of Formula (II) or a pharmaceutically
acceptable salt thereof are also useful for causing
immunosuppression in a patient in need thereof. The compositions
comprising a pharmaceutically acceptable carrier and a compound of
Formula (III) or a pharmaceutically acceptable salt thereof are
also useful for treating or preventing an autoimmune disorder in a
patient in need of such treatment or prevention.
[0050] The invention further provides methods for treating or
preventing cancer or neoplastic disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (III) or a
pharmaceutically acceptable salt thereof.
[0051] The invention further provides methods for inhibiting the
growth of a cancer cell or neoplastic cell comprising contacting a
cancer cell or neoplastic cell with an effective amount of a
compound having the general Formula (III) or a pharmaceutically
acceptable salt thereof.
[0052] The invention further provides methods for treating or
preventing a viral infection in a patient comprising administering
to a patient in need of such treatment or prevention an effective
amount of a compound of Formula (III) or a pharmaceutically
acceptable salt thereof.
[0053] The invention further provides methods for inhibiting the
replication or infectivity of a virus comprising contacting a virus
or a virus-infected cell with an effective amount of a compound
having the general Formula (III) or a pharmaceutically acceptable
salt thereof.
[0054] The invention further provides methods for causing
immunosuppression in a patient comprising administering to a
patient in need thereof an effective amount of a compound of
Formula (III) or a pharmaceutically acceptable salt thereof.
[0055] The invention further provides methods for treating or
preventing an autoimmune disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (III) or a
pharmaceutically acceptable salt thereof.
Formula IV
[0056] The present invention encompasses novel compounds having the
general Formula (IV): 4
[0057] and pharmaceutically acceptable salts thereof, wherein:
[0058] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, and --C(O)OCH.sub.2C.sub.6H.sub.5;
[0059] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl, or
--CH.sub.2C.sub.6H.sub.5, the --CH.sub.2C.sub.6H.sub.5 being
unsubstituted or substituted on the phenyl with one or more
methoxyl, halogen, methyl, nitro, trifluoromethyl, or
methoxylcarbonyl groups;
[0060] R.sub.3 is --CH.sub.3, --CH.sub.2CH.sub.3, or
--C.sub.6H.sub.5;
[0061] R.sub.4 is a C.sub.1-C.sub.15 straight chain alkyl,
-2-pyrrolyl, -3-pyrrolyl, -2-furanyl, -3-furanyl, or
--C.sub.6H.sub.5, the --C.sub.6H.sub.5 being unsubstituted or
substituted with one or more methyl, methoxyl, halogen,
trifluoromethyl, or methoxycarbonyl groups,
[0062] R.sub.8 is --H, --CH.sub.3, --CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.3, or --(CH.sub.2).sub.3CH.sub.3; and
[0063] m is 1 to 4.
[0064] The compounds of Formula (IV) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. The compounds of Formula (IV) or a pharmaceutically
acceptable salt thereof are also useful for inhibiting the growth
of a cancer cell or neoplastic cell. The compounds of Formula (IV)
or a pharmaceutically acceptable salt thereof are useful for
treating or preventing a viral infection in a patient in need of
such treatment or prevention. The compounds of Formula (IV) or a
pharmaceutically acceptable salt thereof are also useful for
inhibiting the replication or infectivity of a virus. The compounds
of Formula (IV) or a pharmaceutically acceptable salt thereof are
also useful for inhibiting the replication or infectivity of a
virus. The compounds of Formula (IV) or a pharmaceutically
acceptable salt thereof are also useful for causing
immunosuppression in a patient in need thereof. The compounds of
Formula (IV) or a pharmaceutically acceptable salt thereof are also
useful for treating or preventing an autoimmune disorder in a
patient in need of such treatment or prevention.
[0065] The present invention provides compositions comprising a
pharmaceutically acceptable carrier and an effective amount of a
compound of Formula (IV) or a pharmaceutically acceptable salt
thereof. The compositions comprising a pharmaceutically acceptable
carrier and a compound of Formula (IV) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. These compositions are also useful for inhibiting
the growth of a cancer cell or neoplastic cell. The compositions
comprising a pharmaceutically acceptable carrier and a compound of
Formula (IV) or a pharmaceutically acceptable salt thereof are also
useful for treating or preventing a viral infection in a patient in
need of such treatment or prevention. These compositions are also
useful for inhibiting the replication or infectivity of a virus.
The compositions comprising a pharmaceutically acceptable carrier
and a compound of Formula (IV) or a pharmaceutically acceptable
salt thereof are also useful for causing immunosuppression in a
patient in need thereof. The compositions comprising a
pharmaceutically acceptable carrier and a compound of Formula (IV)
or a pharmaceutically acceptable salt thereof are also useful for
treating or preventing an autoimmune disorder in a patient in need
of such treatment or prevention.
[0066] The invention further provides methods for treating or
preventing cancer or neoplastic disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (IV) or a
pharmaceutically acceptable salt thereof.
[0067] The invention further provides methods for inhibiting the
growth of a cancer cell or neoplastic cell comprising contacting a
cancer cell or neoplastic cell with an effective amount of a
compound having the general Formula (IV) or a pharmaceutically
acceptable salt thereof.
[0068] The invention further provides methods for treating or
preventing a viral infection in a patient comprising administering
to a patient in need of such treatment or prevention an effective
amount of a compound of Formula (IV) or a pharmaceutically
acceptable salt thereof.
[0069] The invention further provides methods for inhibiting the
replication or infectivity of a virus comprising contacting a virus
or a virus-infected cell with an effective amount of a compound
having the general Formula (IV) or a pharmaceutically acceptable
salt thereof.
[0070] The invention further provides methods for causing
immunosuppression in a patient comprising administering to a
patient in need thereof an effective amount of a compound of
Formula (IV) or a pharmaceutically acceptable salt thereof.
[0071] The invention further provides methods for treating or
preventing an autoimmune disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (IV) or a
pharmaceutically acceptable salt thereof.
Formula V
[0072] The present invention encompasses novel compounds having the
general Formula (V): 5
[0073] and pharmaceutically acceptable salts thereof, wherein:
[0074] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, and --C(O)OCH.sub.2C.sub.6H.sub.5;
[0075] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl, or
--CH.sub.2C.sub.6H.sub.5, the --CH.sub.2C.sub.6H.sub.5 being
unsubstituted substituted on the phenyl with one or more methoxyl,
halogen, methyl, nitro, trifluoromethyl, or methoxylcarbonyl
groups;
[0076] R.sub.3 is --CH.sub.3, --CH.sub.2CH.sub.3, or
--C.sub.6H.sub.5;
[0077] R.sub.7 is --H, a C.sub.1-C.sub.10 straight chain alkyl, or
--CH(CH.sub.3).sub.2; and
[0078] n is 4 to 8.
[0079] The compounds of Formula (V) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. The compounds of Formula (V) or a pharmaceutically
acceptable salt thereof are also useful for inhibiting the growth
of a cancer cell or neoplastic cell. The compounds of Formula (V)
or a pharmaceutically acceptable salt thereof are useful for
treating or preventing a viral infection in a patient in need of
such treatment or prevention. The compounds of Formula (V) or a
pharmaceutically acceptable salt thereof are also useful for
inhibiting the replication or infectivity of a virus. The compounds
of Formula (V) or a pharmaceutically acceptable salt thereof are
also useful for causing immunosuppression in a patient in need
thereof. The compounds of Formula (V) or a pharmaceutically
acceptable salt thereof are also useful for treating or preventing
an autoimmune disorder in a patient in need of such treatment or
prevention.
[0080] The present invention provides compositions comprising a
pharmaceutically acceptable carrier and an effective amount of a
compound of Formula (V) or a pharmaceutically acceptable salt
thereof. The compositions comprising a pharmaceutically acceptable
carrier and a compound of Formula (V) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. These compositions are also useful for inhibiting
the growth of a cancer cell or neoplastic cell. The compositions
comprising a pharmaceutically acceptable carrier and a compound of
Formula (V) or a pharmaceutically acceptable salt thereof are also
useful for treating or preventing a viral infection in a patient in
need of such treatment or prevention. These compositions are also
useful for inhibiting the replication or infectivity of a virus.
The compositions comprising a pharmaceutically acceptable carrier
and a compound of Formula (V) or a pharmaceutically acceptable salt
thereof are also useful for causing immunosuppression in a patient
in need thereof. The compositions comprising a pharmaceutically
acceptable carrier and a compound of Formula (V) or a
pharmaceutically acceptable salt thereof are also useful for
treating or preventing an autoimmune disorder in a patient in need
of such treatment or prevention.
[0081] The invention further provides methods for treating or
preventing cancer or neoplastic disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (V) or a
pharmaceutically acceptable salt thereof.
[0082] The invention further provides methods for inhibiting the
growth of a cancer cell or neoplastic cell comprising contacting a
cancer cell or neoplastic cell with an effective amount of a
compound having the general Formula (V) or a pharmaceutically
acceptable salt thereof.
[0083] The invention further provides methods for treating or
preventing a viral infection in a patient comprising administering
to a patient in need of such treatment or prevention an effective
amount of a compound of Formula (V) or a pharmaceutically
acceptable salt thereof.
[0084] The invention further provides methods for inhibiting the
replication or infectivity of a virus comprising contacting a virus
or a virus-infected cell with an effective amount of a compound
having the general Formula (V) or a pharmaceutically acceptable
salt thereof.
[0085] The invention further provides methods for causing
immunosuppression in a patient comprising administering to a
patient in need thereof an effective amount of a compound of
Formula (V) or a pharmaceutically acceptable salt thereof.
[0086] The invention further provides methods for treating or
preventing an autoimmune disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (V) or a
pharmaceutically acceptable salt thereof.
Formula VI
[0087] The present invention encompasses novel compounds having the
general Formula (VI): 6
[0088] and pharmaceutically acceptable salts thereof, wherein:
[0089] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5;
[0090] R.sub.3 is a C.sub.1-C.sub.10 straight chain alkyl,
--CH(CH.sub.3).sub.2, --CH(CH.sub.3)CH.sub.2CH.sub.3,
--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.3,
--CH(OH)CH.sub.2CH.sub.2CH.sub.3, --CH(Cl)CH.sub.2CH.sub.2CH.sub.3,
or --CH.sub.2C.sub.6H.sub.5; and
[0091] n is 1 to 5.
[0092] The compounds of Formula (VI) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. The compounds of Formula (VI) or a pharmaceutically
acceptable salt thereof are also useful for inhibiting the growth
of a cancer cell or neoplastic cell. The compounds of Formula (VI)
or a pharmaceutically acceptable salt thereof are useful for
treating or preventing a viral infection in a patient in need of
such treatment or prevention. The compounds of Formula (VI) or a
pharmaceutically acceptable salt thereof are also useful for
inhibiting the replication or infectivity of a virus. The compounds
of Formula (VI) or a pharmaceutically acceptable salt thereof are
also useful for causing immunosuppression in a patient in need
thereof. The compounds of Formula (VI) or a pharmaceutically
acceptable salt thereof are also useful for treating or preventing
an autoimmune disorder in a patient in need of such treatment or
prevention.
[0093] The present invention provides compositions comprising a
pharmaceutically acceptable carrier and an effective amount of a
compound of Formula (VI) or a pharmaceutically acceptable salt
thereof. The compositions comprising a pharmaceutically acceptable
carrier and a compound of Formula (VI) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. These compositions are also useful for inhibiting
the growth of a cancer cell or neoplastic cell. The compositions
comprising a pharmaceutically acceptable carrier and a compound of
Formula (VI) or a pharmaceutically acceptable salt thereof are also
useful for treating or preventing a viral infection in a patient in
need of such treatment or prevention. These compositions are also
useful for inhibiting the replication or infectivity of a virus.
The compositions comprising a pharmaceutically acceptable carrier
and a compound of Formula (VI) or a pharmaceutically acceptable
salt thereof are also useful for causing immunosuppression in a
patient in need thereof. The compositions comprising a
pharmaceutically acceptable carrier and a compound of Formula (VI)
or a pharmaceutically acceptable salt thereof are also useful for
treating or preventing an autoimmune disorder in a patient in need
of such treatment or prevention.
[0094] The invention further provides methods for treating or
preventing cancer or neoplastic disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (VI) or a
pharmaceutically acceptable salt thereof.
[0095] The invention further provides methods for inhibiting the
growth of a cancer cell or neoplastic cell comprising contacting a
cancer cell or neoplastic cell with an effective amount of a
compound having the general Formula (VI) or a pharmaceutically
acceptable salt thereof.
[0096] The invention further provides methods for treating or
preventing a viral infection in a patient comprising administering
to a patient in need of such treatment or prevention an effective
amount of a compound of Formula (VI) or a pharmaceutically
acceptable salt thereof.
[0097] The invention further provides methods for inhibiting the
replication or infectivity of a virus comprising a contacting virus
or a virus-infected cell with an effective amount of a compound
having the general Formula (VI) or a pharmaceutically acceptable
salt thereof.
[0098] The invention further provides methods for causing
immunosuppression in a patient comprising administering to a
patient in need thereof an effective amount of a compound of
Formula (VI) or a pharmaceutically acceptable salt thereof.
[0099] The invention further provides methods for treating or
preventing an autoimmune disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (VI) or a
pharmaceutically acceptable salt thereof.
Formula VII
[0100] The present invention encompasses novel compounds having the
general Formula (VII): 7
[0101] and pharmaceutically acceptable salts thereof, wherein:
[0102] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5; and
[0103] R.sub.4 is --H or a C.sub.1-C.sub.15 straight chain
alkyl.
[0104] The compounds of Formula (VII) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. The compounds of Formula (VII) or a pharmaceutically
acceptable salt thereof are also useful for inhibiting the growth
of a cancer cell or neoplastic cell. The compounds of Formula (VII)
or a pharmaceutically acceptable salt thereof are useful for
treating or preventing a viral infection in a patient in need of
such treatment or prevention. The compounds of Formula (VII) or a
pharmaceutically acceptable salt thereof are also useful for
inhibiting the replication or infectivity of a virus. The compounds
of Formula (VII) or a pharmaceutically acceptable salt thereof are
also useful for causing immunosuppression in a patient in need
thereof. The compounds of Formula (VII) or a pharmaceutically
acceptable salt thereof are also useful for treating or preventing
an autoimmune disorder in a patient in need of such treatment or
prevention.
[0105] The present invention provides compositions comprising a
pharmaceutically acceptable carrier and an effective amount of a
compound of Formula (VII) or a pharmaceutically acceptable salt
thereof. The compositions comprising a pharmaceutically acceptable
carrier and a compound of Formula (VII) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. These compositions are also useful for inhibiting
the growth of a cancer cell or neoplastic cell. The compositions
comprising a pharmaceutically acceptable carrier and a compound of
Formula (VII) or a pharmaceutically acceptable salt thereof are
also useful for treating or preventing a viral infection in a
patient in need of such treatment or prevention. These compositions
are also useful for inhibiting the replication or infectivity of a
virus. The compositions comprising a pharmaceutically acceptable
carrier and a compound of Formula (VII) or a pharmaceutically
acceptable salt thereof are also useful for causing
immunosuppression in a patient in need thereof. The compositions
comprising a pharmaceutically acceptable carrier and a compound of
Formula (VII) or a pharmaceutically acceptable salt thereof are
also useful for treating or preventing an autoimmune disorder in a
patient in need of such treatment or prevention.
[0106] The invention further provides methods for treating or
preventing cancer or neoplastic disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (VII) or a
pharmaceutically acceptable salt thereof.
[0107] The invention further provides methods for inhibiting the
growth of a cancer cell or neoplastic cell comprising contacting a
cancer cell or neoplastic cell with an effective amount of a
compound having the general Formula (VII) or a pharmaceutically
acceptable salt thereof.
[0108] The invention further provides methods for treating or
preventing a viral infection in a patient comprising administering
to a patient in need of such treatment or prevention an effective
amount of a compound of Formula (VII) or a pharmaceutically
acceptable salt thereof.
[0109] The invention further provides methods for inhibiting the
replication or infectivity of a virus comprising contacting a virus
or a virus-infected cell with an effective amount of a compound
having the general Formula (VII) or a pharmaceutically acceptable
salt thereof.
[0110] The invention further provides methods for causing
immunosuppression in a patient comprising administering to a
patient in need thereof an effective amount of a compound of
Formula (VII) or a pharmaceutically acceptable salt thereof.
[0111] The invention further provides methods for treating or
preventing an autoimmune disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (VII) or a
pharmaceutically acceptable salt thereof.
Formula VIII
[0112] The present invention encompasses novel compounds having the
general Formula (VIII): 8
[0113] and pharmaceutically acceptable salts thereof, wherein:
[0114] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5;
[0115] R.sub.4 is --H or a C.sub.1-C.sub.10 straight chain
alkyl;
[0116] R.sub.5 is --H or a C.sub.1-C.sub.10 straight chain
alkyl;
[0117] and
[0118] m is 1 to 4.
[0119] The compounds of Formula (VIII) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. The compounds of Formula (VIII) or a
pharmaceutically acceptable salt thereof are also useful for
inhibiting the growth of a cancer cell or neoplastic cell. The
compounds of Formula (VIII) or a pharmaceutically acceptable salt
thereof are useful for treating or preventing a viral infection in
a patient in need of such treatment or prevention. The compounds of
Formula (VIII) or a pharmaceutically acceptable salt thereof are
also useful for inhibiting the replication or infectivity of a
virus. The compounds of Formula (VII) or a pharmaceutically
acceptable salt thereof are also useful for causing
immunosuppression in a patient in need thereof. The compounds of
Formula (VIII) or a pharmaceutically acceptable salt thereof are
also useful for treating or preventing an autoimmune disorder in a
patient in need of such treatment or prevention.
[0120] The present invention provides compositions comprising a
pharmaceutically acceptable carrier and an effective amount of a
compound of Formula (VIII) or a pharmaceutically acceptable salt
thereof. The compositions comprising a pharmaceutically acceptable
carrier and a compound of Formula (VIII) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. These compositions are also useful for inhibiting
the growth of a cancer cell or neoplastic cell. The compositions
comprising a pharmaceutically acceptable carrier and a compound of
Formula (VIII) or a pharmaceutically acceptable salt thereof are
also useful for treating or preventing a viral infection in a
patient in need of such treatment or prevention. These compositions
are also useful for inhibiting the replication or infectivity of a
virus. The compositions comprising a pharmaceutically acceptable
carrier and a compound of Formula (VIII) or a pharmaceutically
acceptable salt thereof are also useful for causing
immunosuppression in a patient in need thereof. The compositions
comprising a pharmaceutically acceptable carrier and a compound of
Formula (VIII) or a pharmaceutically acceptable salt thereof are
also useful for treating or preventing an autoimmune disorder in a
patient in need of such treatment or prevention.
[0121] The invention further provides methods for treating or
preventing cancer or neoplastic disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (VIII) or a
pharmaceutically acceptable salt thereof.
[0122] The invention further provides methods for inhibiting the
growth of a cancer cell or neoplastic cell comprising contacting a
cancer cell or neoplastic cell with an effective amount of a
compound having the general Formula (VIII) or a pharmaceutically
acceptable salt thereof.
[0123] The invention further provides methods for treating or
preventing a viral infection in a patient comprising administering
to a patient in need of such treatment or prevention an effective
amount of a compound of Formula (VIII) or a pharmaceutically
acceptable salt thereof.
[0124] The invention further provides methods for inhibiting the
replication or infectivity of a virus comprising contacting a virus
or a virus-infected cell with an effective amount of a compound
having the general Formula (VIII) or a pharmaceutically acceptable
salt thereof.
[0125] The invention further provides methods for causing
immunosuppression in a patient comprising administering to a
patient in need thereof an effective amount of a compound of
Formula (VIII) or a pharmaceutically acceptable salt thereof.
[0126] The invention further provides methods for treating or
preventing an autoimmune disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (VIII) or a
pharmaceutically acceptable salt thereof.
Formula IX
[0127] The present invention encompasses novel compounds having the
general Formula (IX): 9
[0128] and pharmaceutically acceptable salts thereof, wherein:
[0129] R.sub.1 is --H, --CH.sub.3, --SO.sub.2-4-methylphenyl,
--CH.sub.2C.sub.6H.sub.5, --Si(R.sub.5R.sub.6R.sub.7),
--CH.sub.2OCH.sub.2CH.sub.2SiCH.sub.3, --C(O)OC(CH.sub.3).sub.3, or
--C(O)CH.sub.2C.sub.6H.sub.5;
[0130] R.sub.2 is --CH.sub.3, --CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub- .3, or --CH.sub.2C.sub.6H.sub.5;
[0131] R.sub.3 is --H or Cl;
[0132] R.sub.4 is --H or a C.sub.1-C.sub.10 straight chain
alkyl;
[0133] R.sub.5 is a C.sub.1-C.sub.4 straight or branched chain
alkyl or --C.sub.6H.sub.5;
[0134] R.sub.6 is a C.sub.1-C.sub.3 straight or branched chain
alkyl;
[0135] R.sub.7 is a C.sub.1-C.sub.3 straight or branched chain
alkyl; and
[0136] n is 1 to 5.
[0137] The compounds of Formula (IX) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. The compounds of Formula (IX) or a pharmaceutically
acceptable salt thereof are also useful for inhibiting the growth
of a cancer cell or neoplastic cell. The compounds of Formula (IX)
or a pharmaceutically acceptable salt thereof are useful for
treating or preventing a viral infection in a patient in need of
such treatment or prevention. The compounds of Formula (IX) or a
pharmaceutically acceptable salt thereof are also useful for
inhibiting the replication or infectivity of a virus. The compounds
of Formula (IX) or a pharmaceutically acceptable salt thereof are
also useful for causing immunosuppression in a patient in need
thereof. The compounds of Formula (IX) or a pharmaceutically
acceptable salt thereof are also useful for treating or preventing
an autoimmune disorder in a patient in need of such treatment or
prevention.
[0138] The present invention provides compositions comprising a
pharmaceutically acceptable carrier and an effective amount of a
compound of Formula (IX) or a pharmaceutically acceptable salt
thereof. The compositions comprising a pharmaceutically acceptable
carrier and a compound of Formula (IX) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. These compositions are also useful for inhibiting
the growth of a cancer cell or neoplastic cell. The compositions
comprising a pharmaceutically acceptable carrier and a compound of
Formula (IX) or a pharmaceutically acceptable salt hereof are also
useful for treating or preventing a viral infection in a patient in
need of such treatment or prevention. These compositions are also
useful for inhibiting the replication or infectivity of a virus.
The compositions comprising a pharmaceutically acceptable carrier
and a compound of Formula (IX) or a pharmaceutically acceptable
salt thereof are also useful for causing immunosuppression in a
patient in need thereof. The compositions comprising a
pharmaceutically acceptable carrier and a compound of Formula (IX)
or a pharmaceutically acceptable salt thereof are also useful for
treating or preventing an autoimmune disorder in a patient in need
of such treatment or prevention.
[0139] The invention further provides methods for treating or
preventing cancer or neoplastic disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (IX) or a
pharmaceutically acceptable salt thereof.
[0140] The invention further provides methods for inhibiting the
growth of a cancer cell or neoplastic cell comprising contacting a
cancer cell or neoplastic cell with an effective amount of a
compound having the general Formula (IX) or a pharmaceutically
acceptable salt thereof.
[0141] The invention further provides methods for treating or
preventing a viral infection in a patient comprising administering
to a patient in need of such treatment or prevention an effective
amount of a compound of Formula (IX) or a pharmaceutically
acceptable salt thereof.
[0142] The invention further provides methods for inhibiting the
replication or infectivity of a virus comprising contacting a virus
or a virus-infected cell with an effective amount of a compound
having the general Formula (IX) or a pharmaceutically acceptable
salt thereof.
[0143] The invention further provides methods for causing
immunosuppression in a patient comprising administering to a
patient in need thereof an effective amount of a compound of
Formula (IX) or a pharmaceutically acceptable salt thereof.
[0144] The invention further provides methods for treating or
preventing an autoimmune disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (IX) or a
pharmaceutically acceptable salt thereof.
Formula X
[0145] The present invention encompasses novel compounds having the
general Formula (X): 10
[0146] and pharmaceutically acceptable salts thereof, wherein:
[0147] R.sub.1 is --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--COCH.sub.3, --C(O)OC(CH.sub.3).sub.3, or
--C(O)CH.sub.2C.sub.6H.sub.5;
[0148] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5, the --CH.sub.2C.sub.6H.sub.5 being
unsubstituted or substituted with one or more halogen, methoxyl,
methyl, methoxycarbonyl, or nitro groups;
[0149] R.sub.3is --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5, or
--C(O)OC(CH.sub.3).sub.3;
[0150] R.sub.4 is --H or --CH.sub.3;
[0151] R.sub.5 is --H, --CH.sub.3, --OCH.sub.3, --F, --Cl, --Br,
--I, --CN, --NH.sub.2, --NH(C.sub.1-C.sub.3 straight or branched
chain alkyl), --NHCOCH.sub.3, --NO.sub.2, --COOH, --COOR.sub.6,
--OH, or --OCH.sub.2C.sub.6H.sub.5; and
[0152] R.sub.6 is a C.sub.1-C.sub.6 straight chain alkyl.
[0153] The compounds of Formula (X) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. The compounds of Formula (X) or a pharmaceutically
acceptable salt thereof are also useful for inhibiting the growth
of a cancer cell or neoplastic cell. The compounds of Formula (X)
or a pharmaceutically acceptable salt thereof are useful for
treating or preventing a viral infection in a patient in need of
such treatment or prevention. The compounds of Formula (X) or a
pharmaceutically acceptable salt thereof are also useful for
inhibiting the replication or infectivity of a virus. The compounds
of Formula (X) or a pharmaceutically acceptable salt thereof are
also useful for causing immunosuppression in a patient in need
thereof. The compounds of Formula (X) or a pharmaceutically
acceptable salt thereof are also useful for treating or preventing
an autoimmune disorder in a patient in need of such treatment or
prevention.
[0154] The present invention provides compositions comprising a
pharmaceutically acceptable carrier and an effective amount of a
compound of Formula (X) or a pharmaceutically acceptable salt
thereof. The compositions comprising a pharmaceutically acceptable
carrier and a compound of Formula (X) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. These compositions are also useful for inhibiting
the growth of a cancer cell or neoplastic cell. The compositions
comprising a pharmaceutically acceptable carrier and a compound of
Formula (X) or a pharmaceutically acceptable salt thereof are also
useful for treating or preventing a viral infection in a patient in
need of such treatment or prevention. These compositions are also
useful for inhibiting the replication or infectivity of a virus.
The compositions comprising a pharmaceutically acceptable carrier
and a compound of Formula (X) or a pharmaceutically acceptable salt
thereof are also useful for causing immunosuppression in a patient
in need thereof. The compositions comprising a pharmaceutically
acceptable carrier and a compound of Formula (X) or a
pharmaceutically acceptable salt thereof are also useful for
treating or preventing an autoimmune disorder in a patient in need
of such treatment or prevention.
[0155] The invention further provides methods for treating or
preventing cancer or neoplastic disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (X) or a
pharmaceutically acceptable salt thereof.
[0156] The invention further provides methods for inhibiting the
growth of a cancer cell or neoplastic cell comprising contacting a
cancer cell or neoplastic cell with an effective amount of a
compound having the general Formula (X) or a pharmaceutically
acceptable salt thereof.
[0157] The invention further provides methods for treating or
preventing a viral infection in a patient comprising administering
to a patient in need of such treatment or prevention an effective
amount of a compound of Formula (X) or a pharmaceutically
acceptable salt thereof.
[0158] The invention further provides methods for inhibiting the
replication or infectivity of a virus comprising contacting a virus
or a virus-infected cell with an effective amount of a compound
having the general Formula (X) or a pharmaceutically acceptable
salt thereof.
[0159] The invention further provides methods for causing
immunosuppression in a patient comprising administering to a
patient in need thereof an effective amount of a compound of
Formula (X) or a pharmaceutically acceptable salt thereof.
[0160] The invention further provides methods for treating or
preventing an autoimmune disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (XI) or a
pharmaceutically acceptable salt thereof.
Formula XI
[0161] The present invention encompasses novel compounds having the
general Formula (XI): 11
[0162] and pharmaceutically acceptable salts thereof, wherein:
[0163] R.sub.1 is --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--COCH.sub.3, --C(O)OC(CH.sub.3).sub.3, or
--C(O)CH.sub.2C.sub.6H.sub.5;
[0164] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5;
[0165] R.sub.3 is --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, or --C(O)CH.sub.2C.sub.6H.sub.5;
[0166] R.sub.4 is --H or --CH.sub.3;
[0167] R.sub.5 is --H, a C.sub.1-C.sub.10 straight chain alkyl,
--OR.sub.6, --F, --Cl, --Br, --I, --CN, --COOH, --COOR.sub.6,
--NH.sub.2, --NHCOR.sub.6, --NO.sub.2, --OH, or
--OCH.sub.2C.sub.6H.sub.5; and
[0168] R.sub.6 is a C.sub.1-C.sub.6 straight chain alkyl.
[0169] The compounds of Formula (XI) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. The compounds of Formula (XI) or a pharmaceutically
acceptable salt thereof are also useful for inhibiting the growth
of a cancer cell or neoplastic cell. The compounds of Formula (XI)
or a pharmaceutically acceptable salt thereof are useful for
treating or preventing a viral infection in a patient in need of
such treatment or prevention. The compounds of Formula (XI) or a
pharmaceutically acceptable salt thereof are also useful for
inhibiting the replication or infectivity of a virus. The compounds
of Formula (XI) or a pharmaceutically acceptable salt thereof are
also useful for causing immunosuppression in a patient in need
thereof. The compounds of Formula (XI) or a pharmaceutically
acceptable salt thereof are also useful for treating or preventing
an autoimmune disorder in a patient in need of such treatment or
prevention.
[0170] The present invention provides compositions comprising a
pharmaceutically acceptable carrier and an effective amount of a
compound of Formula (XI) or a pharmaceutically acceptable salt
thereof. The compositions comprising a pharmaceutically acceptable
carrier and a compound of Formula (XI) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. These compositions are also useful for inhibiting
the growth of a cancer cell or neoplastic cell. The compositions
comprising a pharmaceutically acceptable carrier and a compound of
Formula (XI) or a pharmaceutically acceptable salt thereof are also
useful for treating or preventing a viral infection in a patient in
need of such treatment or prevention. These compositions are also
useful for inhibiting the replication or infectivity of a virus.
The compositions comprising a pharmaceutically acceptable carrier
and a compound of Formula (XI) or a pharmaceutically acceptable
salt thereof are also useful for causing immunosuppression in a
patient in need thereof. The compositions comprising a
pharmaceutically acceptable carrier and compound of Formula (XI) or
a pharmaceutically acceptable salt thereof are also useful for
treating or preventing an autoimmune disorder in a patient in need
of such treatment or prevention.
[0171] The invention further provides methods for treating or
preventing cancer or neoplastic disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (XI) or a
pharmaceutically acceptable salt thereof.
[0172] The invention further provides methods for inhibiting the
growth of a cancer cell or neoplastic cell comprising contacting a
cancer cell or neoplastic cell with an effective amount of a
compound having the general Formula (XI) or a pharmaceutically
acceptable salt thereof.
[0173] The invention further provides methods for treating or
preventing a viral infection in a patient comprising administering
to a patient in need of such treatment or prevention an effective
amount of a compound of Formula (XI) or a pharmaceutically
acceptable salt thereof.
[0174] The invention further provides methods for inhibiting the
replication or infectivity of a virus comprising contacting a virus
or a virus-infected cell with an effective amount of a compound
having the general Formula (XI) or a pharmaceutically acceptable
salt thereof.
[0175] The invention further provides methods for causing
immunosuppression in a patient comprising administering to a
patient in need thereof an effective amount of a compound of
Formula (XI) or a pharmaceutically acceptable salt thereof.
[0176] The invention further provides methods for treating or
preventing an autoimmune disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (XI) or a
pharmaceutically acceptable salt thereof.
Formula XII
[0177] The present invention encompasses novel compounds having the
general Formula (XII): 12
[0178] and pharmaceutically acceptable salts thereof, wherein:
[0179] R.sub.1 is --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5, or
--C(O)OC(CH.sub.3).sub.3;
[0180] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5;
[0181] R.sub.3 is --H, --SO.sub.2CH.sub.3,
--SO.sub.2C.sub.6H.sub.5, --C(O)OC(CH.sub.3).sub.3, --COCH.sub.3,
--CO(CH.sub.2).sub.4CH.sub.3, --CO(CH.sub.2).sub.8CH.sub.3,
--COC.sub.6H.sub.5, --CO-4-(NHCOC.sub.6H.su- b.5)C.sub.6H.sub.4,
--CO-2-pyridyl, --CO-2-napthyl, --CO-2-quinolyl,
--CO-6-(NHCO(CH.sub.2).sub.4CH.sub.3)-2-quinolyl, --CO-2-pyrrolyl,
--CO-2-indolyl, --CO-1-methyl-2-indolyl, --CO-2-benzofuranyl,
--CO-2-benzothiophenyl, --CO-3-methyl-2-indenyl, or
--CO--R.sub.4-2-indolyl; and
[0182] R.sub.4 is -5-OCH.sub.3, -6-OH-7-OCH.sub.3, -5-NHCONH.sub.2,
5-NHCOC.sub.6H.sub.5, -5-NHCO-indolyl, -5-NHCO-2-benzofuranyl,
-5-NHCO-5(NHCONH.sub.2)-2-indolyl, or
-5-NHCO-5-(NHCOC.sub.6H.sub.5)-2-in- dolyl.
[0183] The compounds of Formula (XII) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. The compounds of Formula (XII) or a pharmaceutically
acceptable salt thereof are also useful for inhibiting the growth
of a cancer cell or neoplastic cell. The compounds of Formula (XII)
or a pharmaceutically acceptable salt thereof are useful for
treating or preventing a viral infection in a patient in need of
such treatment or prevention. The compounds of Formula (XII) or a
pharmaceutically acceptable salt thereof are also useful for
inhibiting the replication or infectivity of a virus. The compounds
of Formula (XII) or a pharmaceutically acceptable salt thereof are
also useful for causing immunosuppression in a patient in need
thereof. The compounds of Formula (XII) or a pharmaceutically
acceptable salt thereof are also useful for treating or preventing
an autoimmune disorder in a patient in need of such treatment or
prevention.
[0184] The present invention provides compositions comprising a
pharmaceutically acceptable carrier and an effective amount of a
compound of Formula (XII) or a
[0185] harmaceutically acceptable salt thereof. The compositions
comprising a pharmaceutically acceptable carrier and a compound of
Formula (XII) or a pharmaceutically acceptable salt thereof are
useful for treating or preventing cancer or neoplastic disease in a
patient in need of such treatment or prevention. These compositions
are also useful for inhibiting the growth of a cancer cell or
neoplastic cell. The compositions comprising a pharmaceutically
acceptable carrier and a compound of Formula (XII) or a
pharmaceutically acceptable salt thereof are also useful for
treating or preventing a viral infection in a patient in need of
such treatment or prevention. These compositions are also useful
for inhibiting the replication or infectivity of a virus. The
compositions comprising a pharmaceutically acceptable carrier and a
compound of Formula (XII) or a pharmaceutically acceptable salt
thereof are also useful for causing immunosuppression in a patient
in need thereof. The compositions comprising a pharmaceutically
acceptable carrier and a compound of Formula (XII) or a
pharmaceutically acceptable salt thereof are also useful for
treating or preventing an autoimmune disorder in a patient in need
of such treatment or prevention.
[0186] The invention further provides methods for treating or
preventing cancer or neoplastic disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (XII) or a
pharmaceutically acceptable salt thereof.
[0187] The invention further provides methods for inhibiting the
growth of a cancer cell or neoplastic cell comprising contacting a
cancer cell or neoplastic cell with an effective amount of a
compound having the general Formula (XII) or a pharmaceutically
acceptable salt thereof.
[0188] The invention further provides methods for treating or
preventing a viral infection in a patient comprising administering
to a patient in need of such treatment or prevention an effective
amount of a compound of Formula (XII) or a pharmaceutically
acceptable salt thereof.
[0189] The invention further provides methods for inhibiting the
replication or infectivity of a virus comprising contacting a virus
or a virus-infected cell with an effective amount of a compound
having the general Formula (XII) or a pharmaceutically acceptable
salt thereof.
[0190] The invention further provides methods for causing
immunosuppression in a patient comprising administering to a
patient in need thereof an effective amount of a compound of
Formula (XII) or a pharmaceutically acceptable salt thereof.
[0191] The invention further provides methods for treating or
preventing an autoimmune disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (XII) or a
pharmaceutically acceptable salt thereof.
Formula XIII
[0192] The present invention encompasses novel compounds having the
general Formula (XII): 13
[0193] and pharmaceutically acceptable salts thereof, wherein:
[0194] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, or --C(O)OCH.sub.2C.sub.6H.sub.5;
[0195] R.sub.2 is --H or a C.sub.1-C.sub.10 straight chain alkyl;
and
[0196] n is 1 to 4.
[0197] The compounds of Formula (XIII) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. The compounds of Formula (XIII) or a
pharmaceutically acceptable salt thereof are also useful for
inhibiting the growth of a cancer cell or neoplastic cell. The
compounds of Formula (XIII) or a pharmaceutically acceptable salt
thereof are useful for treating or preventing a viral infection in
a patient in need of such treatment or prevention. The compounds of
Formula (XIII) or a pharmaceutically acceptable salt thereof are
also useful for inhibiting the replication or infectivity of a
virus. The compounds of Formula (XIII) or a pharmaceutically
acceptable salt thereof are also useful for causing
immunosuppression in a patient in need thereof. The compounds of
Formula (XIII) or a pharmaceutically acceptable salt thereof are
also useful for treating or preventing an autoimmune disorder in a
patient in need of such treatment or prevention.
[0198] The present invention provides compositions comprising a
pharmaceutically acceptable carrier and an effective amount of a
compound of Formula (XIII) or a pharmaceutically acceptable salt
thereof. The compositions comprising a pharmaceutically acceptable
carrier and a compound of Formula (XIII) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. These compositions are also useful for inhibiting
the growth of a cancer cell or neoplastic cell. The compositions
comprising a pharmaceutically acceptable carrier and a compound of
Formula (XIII) or a pharmaceutically acceptable salt thereof are
also useful for treating or preventing a viral infection in a
patient in need of such treatment or prevention. These compositions
are also useful for inhibiting the replication or infectivity of a
virus. The compositions comprising a pharmaceutically acceptable
carrier and a compound of Formula (XIII) or a pharmaceutically
acceptable sals thereof are also useful for causing
immunosuppression in a patient in need thereof. The compositions
comprising a pharmaceutically acceptable carrier and a compound of
Formula (XIII) or a pharmaceutically acceptable salt thereof are
also useful for treating or preventing an autoimmune disorder in a
patient in need of such treatment or prevention.
[0199] The invention further provides methods for treating or
preventing cancer or neoplastic disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (XIII) or a
pharmaceutically acceptable salt thereof.
[0200] The invention further provides methods for inhibiting the
growth of a cancer cell or neoplastic cell comprising contacting a
cancer cell or neoplastic cell with an effective amount of a
compound having the general Formula (XIII) or a pharmaceutically
acceptable salt thereof.
[0201] The invention further provides methods for treating or
preventing a viral infection in a patient comprising administering
to a patient in need of such treatment or prevention an effective
amount of a composition comprising a compound of Formula (XIII) or
a pharmaceutically acceptable salt thereof.
[0202] The invention further provides methods for inhibiting the
replication or infectivity of a virus comprising contacting a virus
or a virus-infected cell with an effective amount of a compound
having the general Formula (XIII) or a pharmaceutically acceptable
salt thereof.
[0203] The invention further provides methods for causing
immunosuppression in a patient comprising administering to a
patient in need thereof an effective amount of a compound of
Formula (XIII) or a pharmaceutically acceptable salt thereof.
[0204] The invention further provides methods for treating or
preventing an autoimmune disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (XIII) or a
pharmaceutically acceptable salt thereof.
[0205] The present invention may be understood more fully by
reference to the following schemes, detailed description, and
illustrative examples which are intended to exemplify non-limiting
embodiments of the invention.
3.1. Definitions and Abbreviations
[0206] Examples of halogens are fluorine, chlorine, bromine, and
iodine.
[0207] Examples of C.sub.1-C.sub.3 straight or branched chain alkyl
groups include, but are not limited to, methyl, ethyl, 1-propyl,
and 2-propyl.
[0208] Examples of C.sub.1-C.sub.4 straight or branched chain alkyl
groups include, but are not limited to, methyl, ethyl, 1-propyl,
2-propyl, 1-butyl, 2-butyl, 2-methyl-1-propyl, and
2-methyl-2-propyl.
[0209] Examples of C,.sub.1-C.sub.6 straight or branched chain
alkyl groups include, but are not limited to, methyl, ethyl,
1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-1-propyl,
2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-1-butyl,
3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 1-hexyl,
2-hexyl, 3-hexyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl,
4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl,
4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, and
2-ethyl-1-butyl.
[0210] Examples of C.sub.1-C.sub.5 straight chain alkyl groups
include, but are not limited to, methyl, ethyl, 1-propyl, 1-butyl,
and 1-pentyl.
[0211] Examples of C.sub.1-C.sub.6 straight chain alkyl groups are
methyl, ethyl, 1-propyl, 1-butyl, 1-pentyl, and 1-hexyl.
[0212] Examples of C.sub.1-C.sub.10 straight chain alkyl groups are
methyl, ethyl, 1-propyl, 1-butyl, 1-pentyl, 1-hexyl, 1-heptyl,
1-octyl, 1-nonyl, and 1-decyl.
[0213] Examples of C.sub.1-C.sub.12 straight chain alkyl groups are
methyl, ethyl, 1-propyl, 1-butyl, 1-pentyl, 1-hexyl, 1-heptyl,
1-octyl, 1-nonyl, 1-decyl, 1-undecyl, and 1-dodecyl.
[0214] Examples of C.sub.1-C.sub.15 straight chain alkyl groups are
methyl, ethyl, 1-propyl, 1-butyl, 1-pentyl, 1-hexyl, 1-heptyl,
1-octyl, 1-nonyl, 1-decyl, 1-undecyl, 1-dodecyl, 1-tridecyl,
1-tetradecyl, and 1-pentadecyl.
[0215] Examples of C.sub.3-C.sub.7 cycloalkyl groups include but
are not limited to cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, and cycloheptyl.
[0216] The following abbreviations and their definitions, unless
defined otherwise, are used in this specification:
1 Abbreviation Definition BOC --C(O)OC(CH.sub.3).sub.3 Cbz
--C(O)OCH.sub.2C.sub.6H.sub.5 THP -2-tetrahydropyranyl MOM
--OCH.sub.2OCH.sub.3 TROC --C(O)OCH.sub.2C(Cl).sub.3 Tf
--SO.sub.2CF.sub.3 Ts --SO.sub.2-4-methyl-C.sub.6H.sub.5 TBDMSCl
tert-butyldimethylsilyl chloride DEAD diethyl azodicarboxylate SEM
2-(trimethylsilyl)ethoxymethyl chloride
--CO-4-(NHCOC.sub.6H.sub.5)C.sub.6H.sub.4 14 --CO-2-pyridyl 15
--CO-2-napthyl 16 --CO-2-quinolyl 17
--CO-6-(NHCO(CH.sub.2).sub.4CH.sub.3)-- 2-quinolyl 18
--CO-2-pyrrolyl 19 --CO-2-indolyl 20 --CO-1-methyl-2-indolyl 21
--CO-2-benzofuranyl 22 --CO-2-benzothiophenyl 23
--CO-3-methyl-2-indenyl 24 --CO-(R.sub.4-2-indolyl) 25 wherein
R.sub.4 can be 6 attached to the 3, 4, 5, 6, or 7 position of the
indole ring.
[0217] When administered to a patient, e.g., a mammal for
veterinary use or a human for clinical use, the Pyrrole-Type
compounds are administered in isolated form. As used herein,
"isolated" means that the Pyrrole-Type compounds are separated from
other components of either (a) a natural source, such as a plant or
cell, preferably bacterial culture, or (b) a synthetic organic
chemical reaction mixture. Preferably, via conventional techniques,
the Pyrrole-Type compounds are purified. As used herein, "purified"
means that when isolated, the isolate contains at least 95%,
preferably at least 98%, of a single Pyrrole-Type compound by
weight of the isolate.
4. BRIEF DESCRIPTION OF THE DRAWINGS
[0218] FIG. 1 is a bar graph depicting cell survival following 72
hours of Compound 79
(4-methoxy-5-(1H-indol-2yl-methylene)-2,2'-bi-1H-pyrrole)
treatment.
5. DETAILED DESCRIPTION OF THE INVENTION
5.1. Formula I
[0219] The present invention encompasses novel compounds having the
general Formula (I) and pharmaceutically acceptable salts thereof,
wherein:
[0220] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, and --C(O)OCH.sub.2C.sub.6H.sub.5;
and
[0221] n is an integer ranging from 1 and 5.
[0222] The compounds of Formula (I) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. The compounds of Formula (I) or a pharmaceutically
acceptable salt thereof are also useful for inhibiting the growth
of a cancer cell or neoplastic cell. The compounds of Formula (I)
or a pharmaceutically acceptable salt thereof are useful for
treating or preventing a viral infection in a patient in need of
such treatment or prevention. The compounds of Formula (I) or a
pharmaceutically acceptable salt thereof are also useful for
inhibiting the replication or infectivity of a virus. The compounds
of Formula (I) or a pharmaceutically acceptable salt thereof are
also useful for causing immunosuppression in a patient in need
thereof. The compounds of Formula (I) or a pharmaceutically
acceptable salt thereof are also useful for treating an autoimmune
disease in a patient in need of such treatment or prevention.
[0223] A preferred subclass of the compounds of Formula (I) is that
wherein:
[0224] each R.sub.1 is independently selected from the group
consisting of --H and --CH.sub.3; and
[0225] n is an integer ranging from 1 to 5.
[0226] A more preferred subclass of the compounds of Formula (I) is
that wherein:
[0227] R.sub.1 is --H; and
[0228] n is an integer ranging from 1 to 3.
[0229] The present invention also provides compositions comprising
a pharmaceutically acceptable carrier and an effective amount of a
compound of Formula (I) or a pharmaceutically acceptable salt
thereof, wherein, in the compound of Formula (I):
[0230] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, and --C(O)OCH.sub.2C.sub.6H.sub.5;
and
[0231] n is an integer ranging from 1 and 5.
[0232] The compositions comprising a pharmaceutically acceptable
carrier and a compound of Formula (I) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. These compositions are also useful for inhibiting
the growth of a cancer cell or neoplastic cell. The compositions
comprising a pharmaceutically acceptable carrier and a compound of
Formula (I) or a pharmaceutically acceptable salt thereof are
useful for treating or preventing a viral infection in a patient in
need of such treatment or prevention. These compositions are also
useful for inhibiting the replication or infectivity of a virus.
The compositions comprising a pharmaceutically acceptable carrier
and a compound of Formula (I) or a pharmaceutically acceptable salt
thereof are also useful for causing immunosuppression in a patient
in need thereof. The compositions comprising a pharmaceutically
acceptable carrier and a compound of Formula (I) or a
pharmaceutically acceptable salt thereof are also useful for
treating an autoimmune disease in a patient in need of such
treatment or prevention.
[0233] A preferred subclass of the compositions comprising a
pharmaceutically acceptable carrier and a compound of Formula (I)
or a pharmaceutically acceptable salt thereof is that wherein, in
the compound of Formula (I):
[0234] each R.sub.1 is independently selected from the group
consisting of --H and --CH.sub.3; and
[0235] n is an integer ranging from 1 to 5.
[0236] A more preferred subclass of the compositions comprising a
pharmaceutically acceptable carrier and a compound of Formula (I)
or a pharmaceutically acceptable salt thereof is that wherein, in
the compound of Formula (I):
[0237] R.sub.1 is --H; and
[0238] n is an integer ranging from 1 to 3.
[0239] The invention further provides methods for treating or
preventing cancer or neoplastic disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (I) or a
pharmaceutically acceptable salt thereof, wherein, in the compound
of Formula (I):
[0240] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, and --C(O)OCH.sub.2C.sub.6H.sub.5;
and
[0241] n is an integer ranging from 1 and 5.
[0242] For use in the methods for treating or preventing cancer or
neoplastic disease, a preferred subclass of the compounds of
Formula (I) is that wherein, in the compound of Formula (I):
[0243] each R.sub.1 is independently selected from the group
consisting of --H and --CH.sub.3; and
[0244] n is an integer ranging from 1 to 5.
[0245] For use in the methods for treating or preventing cancer or
neoplastic disease, a more preferred subclass of the compounds of
Formula (I) is that wherein, in the compound of Formula (I):
[0246] R.sub.1 is --H; and
[0247] n is an integer ranging from 1 to 3.
[0248] The invention further provides methods for inhibiting the
growth of a cancer cell or neoplastic cell comprising contacting a
cancer cell or neoplastic cell with an effective amount of a
compound of general Formula (I) or a pharmaceutically acceptable
salt thereof, wherein, in the compound of Formula (I):
[0249] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, and --C(O)OCH.sub.2C.sub.6H.sub.5;
and
[0250] n is an integer ranging from 1 and 5.
[0251] For use in the methods for inhibiting the growth of a cancer
or neoplastic cell, a preferred subclass of the compounds of
Formula (I) is that wherein, in the compound of Formula (I):
[0252] each R.sub.1 is independently selected from the group
consisting of --H and --CH.sub.3; and
[0253] n is an integer ranging from 1 to 5.
[0254] For use in the methods for inhibiting the growth of a cancer
or neoplastic cell, a more preferred subclass of the compounds of
Formula (I) is that wherein, in the compound of Formula (I):
[0255] R.sub.1 is --H; and
[0256] n is an integer ranging from 1 to 3.
[0257] The invention further provides methods for treating or
preventing a viral infection in a patient comprising administering
to a patient in need of such treatment or prevention an effective
amount of a compound of Formula (I) or a pharmaceutically
acceptable salt thereof, wherein, in the compound of Formula
(I):
[0258] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, and --C(O)OCH.sub.2C.sub.6H.sub.5;
and
[0259] n is an integer ranging from 1 and 5.
[0260] For use in the present methods for treating or preventing a
viral infection, a preferred subclass of the compounds of Formula
(I) is that wherein, in the compound of Formula (I):
[0261] each R.sub.1 is independently selected from the group
consisting of --H and --CH.sub.3; and
[0262] n is an integer ranging from 1 to 5.
[0263] For use in the present methods for treating or preventing a
viral infection, a more preferred subclass of the compounds of
Formula (I) is that wherein, in the compound of Formula (I):
[0264] each R.sub.1 is independently selected from the group
consisting of --H and --CH.sub.3; and
[0265] n is an integer ranging from 1 to 5.
[0266] The invention further provides methods for inhibiting the
replication or infectivity of a virus comprising contacting a virus
or a virus-infected cell with an effective amount of a composition
comprising a pharmaceutically acceptable carrier and a compound of
general Formula (I) or a pharmaceutically acceptable salt thereof,
wherein, in the compound of Formula (I):
[0267] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, and --C(O)OCH.sub.2C.sub.6H.sub.5;
and
[0268] n is an integer ranging from 1 and 5.
[0269] For use in the methods for inhibiting the replication or
infectivity of a virus, a preferred subclass of the compounds of
Formula (I) are those wherein:
[0270] each R.sub.1 is independently selected from the group
consisting of --H and --CH.sub.3; and
[0271] n is an integer ranging from 1 to 5.
[0272] For use in the methods for inhibiting the replication or
infectivity of a virus, a more preferred subclass of the compounds
of Formula (I) are those wherein:
[0273] each R.sub.1 is independently selected from the group
consisting of --H and --CH.sub.3; and
[0274] n is an integer ranging from 1 to 5.
[0275] The invention further provides methods for causing
immunosuppression in a patient comprising administering to a
patient in need thereof an effective amount of a compound of
Formula (I) or a pharmaceutically acceptable salt thereof, wherein,
in the compound of Formula (I):
[0276] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, and --C(O)OCH.sub.2C.sub.6H.sub.5;
and
[0277] n is an integer ranging from 1 and 5.
[0278] For use in the methods of causing immunosuppression, a
preferred subclass of the compounds of Formula (I) are those
wherein:
[0279] each R.sub.1 is independently selected from the group
consisting of --H and --CH.sub.3; and
[0280] n is an integer ranging from 1 to 5.
[0281] For use in the methods of causing immunosuppression, a more
preferred subclass of the compounds of Formula (I) are those
wherein:
[0282] each R.sub.1 is independently selected from the group
consisting of --H and --CH.sub.3; and
[0283] n is an integer ranging from 1 to 5.
[0284] The invention further provides methods for treating or
preventing an autoimmune disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (I) or a
pharmaceutically acceptable salt thereof, wherein, in the compound
of Formula (I):
[0285] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, and --C(O)OCH.sub.2C.sub.6H.sub.5;
and
[0286] n is an integer ranging from 1 and 5.
[0287] For use in the methods of treating or preventing an
autoimmune disease, a preferred subclass of the compounds of
Formula (I) are those wherein:
[0288] each R.sub.1 is independently selected from the group
consisting of --H and --CH.sub.3; and
[0289] n is an integer ranging from 1 to 5.
[0290] For use in the methods of treating or preventing an
autoimmune disease, a more preferred subclass of the compounds of
Formula (I) are those wherein:
[0291] each R.sub.1 is independently selected from the group
consisting of --H and --CH.sub.3; and
[0292] n is an integer ranging from 1 to 5.
5.2. Formula II
[0293] The present invention encompasses novel compounds having the
general Formula (II) and pharmaceutically acceptable salts thereof,
wherein:
[0294] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, and --C(O)OCH.sub.2C.sub.6H.sub.5;
and
[0295] n is an integer ranging from 1 and 5.
[0296] The compounds of Formula (II) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. The compounds of Formula (II) or a pharmaceutically
acceptable salt thereof are also useful for inhibiting the growth
of a cancer cell or neoplastic cell. The compounds of Formula (II)
or a pharmaceutically acceptable salt thereof are useful for
treating or preventing a viral infection in a patient in need of
such treatment or prevention. The compounds of Formula (II) or a
pharmaceutically acceptable salt thereof are also useful for
inhibiting the replication or infectivity of a virus. The compounds
of Formula (II) or a pharmaceutically acceptable salt thereof are
also useful for causing immunosuppression in a patient in need
thereof. The compounds of Formula (II) or a pharmaceutically
acceptable salt thereof are also useful for treating an autoimmune
disease in a patient in need of such treatment or prevention.
[0297] A preferred subclass of the compounds of Formula (II) is
that wherein:
[0298] each R.sub.1 is independently selected from the group
consisting of --H and --CH.sub.3; and
[0299] n is an integer ranging from 1 to 5.
[0300] A more preferred subclass of the compounds of Formula (II)
is that wherein:
[0301] R.sub.1 is --H; and
[0302] n is an integer ranging from 1 to 3.
[0303] The present invention also provides compositions comprising
a pharmaceutically acceptable carrier and an effective amount of a
compound of Formula (II) or a pharmaceutically acceptable salt
thereof, wherein, in the compound of Formula (II):
[0304] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, and --C(O)OCH.sub.2C.sub.6H.sub.5;
and
[0305] n is an integer ranging from 1 and 5.
[0306] The compositions comprising a pharmaceutically acceptable
carrier and a compound of Formula (II) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. These compositions are also useful for inhibiting
the growth of a cancer cell or neoplastic cell. The compositions
comprising a pharmaceutically acceptable carrier and a compound of
Formula (II) or a pharmaceutically acceptable salt thereof are
useful for treating or preventing a viral infection in a patient in
need of such treatment or prevention. These compositions are also
useful for inhibiting the replication or infectivity of a virus.
The compositions comprising a pharmaceutically acceptable carrier
and a compound of Formula (II) or a pharmaceutically acceptable
salt thereof are also useful for causing immunosuppression in a
patient in need thereof. The compositions comprising a
pharmaceutically acceptable carrier and a compound of Formula (II)
or a pharmaceutically acceptable salt thereof are also useful for
treating an autoimmune disease in a patient in need of such
treatment or prevention.
[0307] A preferred subclass of the compositions comprising a
pharmaceutically acceptable carrier and a compound of Formula (II)
or a pharmaceutically acceptable salt thereof is that wherein, in
the compound of Formula (II):
[0308] each R.sub.1 is independently selected from the group
consisting of --H and --CH.sub.3; and
[0309] n is an integer ranging from 1 to 5.
[0310] A more preferred subclass of the compositions comprising a
pharmaceutically acceptable carrier and a compound of Formula (II)
or a pharmaceutically acceptable salt thereof is that wherein, in
the compound of Formula (II):
[0311] R.sub.1 is --H; and
[0312] n is an integer ranging from 1 to 3.
[0313] The invention further provides methods for treating or
preventing cancer or neoplastic disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (II) or a
pharmaceutically acceptable salt thereof, wherein, in the compound
of Formula (II):
[0314] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, and --C(O)OCH.sub.2C.sub.6H.sub.5;
and
[0315] n is an integer ranging from 1 and 5.
[0316] For use in the methods for treating or preventing cancer or
neoplastic disease, a second preferred subclass of the compounds of
Formula (II) is that wherein, in the compound of Formula (II):
[0317] each R.sub.1 is independently selected from the group
consisting of --H and --CH.sub.3; and
[0318] n is an integer ranging from 1 to 5.
[0319] For use in the methods for treating or preventing cancer or
neoplastic disease, a more preferred subclass of the compounds of
Formula (II) is that wherein, in the compound of Formula (II):
[0320] R.sub.1 is --H; and
[0321] n is an integer ranging from 1 to 3.
[0322] The invention further provides methods for inhibiting the
growth of a cancer cell or neoplastic cell comprising contacting a
cancer cell or neoplastic cell with an effective amount of a
compound having the general Formula (II) or a pharmaceutically
acceptable salt thereof, wherein, in the compound of Formula
(II):
[0323] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, and --C(O)OCH.sub.2C.sub.6H.sub.5;
and
[0324] n is an integer ranging from 1 and 5.
[0325] For use in the methods for inhibiting the growth of a cancer
or neoplastic cell, a preferred subclass of the compounds of
Formula (II) is that wherein, in the compound of Formula (II):
[0326] each R.sub.1 is independently selected from the group
consisting of --H and --CH.sub.3; and
[0327] n is an integer ranging from 1 to 5.
[0328] For use in the methods for inhibiting the growth of a cancer
or neoplastic cell, a more preferred subclass of the compounds of
Formula (II) is that wherein, in the compound of Formula (II):
[0329] R.sub.1 is --H; and
[0330] n is an integer ranging from 1 to 3.
[0331] The invention further provides methods for treating or
preventing a viral infection in a patient comprising administering
to a patient in need of such treatment or prevention an effective
amount of a compound of Formula (II) or a pharmaceutically
acceptable salt thereof, wherein, in the compound of Formula
(II):
[0332] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, and --C(O)OCH.sub.2C.sub.6H.sub.5;
[0333] and n is an integer ranging from 1 and 5.
[0334] For use in the present methods for treating or preventing a
viral infection, a preferred subclass of the compounds of Formula
(II) is that wherein, in the compound of Formula (II):
[0335] each R.sub.1 is independently selected from the group
consisting of --H and --CH.sub.3; and
[0336] n is an integer ranging from 1 to 5.
[0337] For use in the present methods for treating or preventing a
viral infection, a more preferred subclass of the compounds of
Formula (II) is that wherein, in the compound of Formula (II):
[0338] each R.sub.1 is independently selected from the group
consisting of --H and --CH.sub.3; and
[0339] n is an integer ranging from 1 to 5.
[0340] The invention further provides methods for inhibiting the
replication or infectivity of a virus comprising contacting a virus
or a virus-infected cell with an effective amount of a compound
having the general Formula (II) or a pharmaceutically acceptable
salt thereof, wherein, in the compound of Formula (II):
[0341] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, and --C(O)OCH.sub.2C.sub.6H.sub.5;
and
[0342] n is an integer ranging from 1 and 5.
[0343] For use in the methods for inhibiting the replication or
infectivity of a virus, a preferred subclass of the compounds of
Formula (II) are those wherein:
[0344] each R.sub.1 is independently selected from the group
consisting of --H and --CH.sub.3; and
[0345] n is an integer ranging from 1 to 5.
[0346] For use in the methods for inhibiting the replication or
infectivity of a virus, a more preferred subclass of the compounds
of Formula (II) are those wherein:
[0347] each R.sub.1 is independently selected from the group
consisting of --H and --CH.sub.3; and
[0348] n is an integer ranging from 1 to 5.
[0349] The invention further provides methods for causing
immunosuppression in a patient comprising administering to a
patient in need thereof an effective amount of a compound of
Formula (II) or a pharmaceutically acceptable salt thereof,
wherein, in the compound of Formula (II):
[0350] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, and --C(O)OCH.sub.2C.sub.6H.sub.5;
and
[0351] n is an integer ranging from 1 and 5.
[0352] For use in the methods for causing immunosuppression, a
preferred subclass of the compounds of Formula (II) are those
wherein:
[0353] each R.sub.1 is independently selected from the group
consisting of --H and --CH.sub.3; and
[0354] n is an integer ranging from 1 to 5.
[0355] For use in the methods for causing immunosuppression, a more
preferred subclass of the compounds of Formula (II) are those
wherein:
[0356] each R.sub.1 is independently selected from the group
consisting of --H and --CH.sub.3; and
[0357] n is an integer ranging from 1 to 5.
[0358] The invention further provides methods for treating or
preventing an autoimmune disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (II) or a
pharmaceutically acceptable salt thereof, wherein, in the compound
of Formula (II):
[0359] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, and --C(O)OCH.sub.2C.sub.6H.sub.5;
and
[0360] n is an integer ranging from 1 and 5.
[0361] For use in the methods for treating or preventing an
autoimmune disease, a preferred subclass of the compounds of
Formula (II) are those wherein:
[0362] each R.sub.1 is independently selected from the group
consisting of --H and --CH.sub.3; and
[0363] n is an integer ranging from 1 to 5.
[0364] For use in the methods for treating or preventing an
autoimmune disease, a more referred subclass of the compounds of
Formula (II) are those wherein:
[0365] each R.sub.1 is independently selected from the group
consisting of --H and --CH.sub.3; and
[0366] n is an integer ranging from 1 to 5.
5.3. Formula III
[0367] The present invention encompasses novel compounds having the
general Formula (III) and pharmaceutically acceptable salts
thereof, wherein:
[0368] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, and --C(O)OCH.sub.2C.sub.6H.sub.5;
[0369] R.sub.2 is a C.sub.1-C.sub.10 straight chain alky or
--CH.sub.2C.sub.6H.sub.5, the --CH.sub.2C.sub.6H.sub.5 being
unsubstituted or substituted on the phenyl with one or more
methoxyl, halogen, methyl, nitro, trifluoromethyl, or
methoxylcarbonyl groups;
[0370] R.sub.3 is --CH.sub.3, --CH.sub.2CH.sub.3, or
--C.sub.6H.sub.5;
[0371] R.sub.4 is --H, a C.sub.1-C.sub.15 straight chain alkyl,
-2-pyrrolyl, -3-pyrrolyl, -2-furanyl, -3-furanyl, or
--C.sub.6H.sub.5, the --C.sub.6H.sub.5 being unsubstituted or
substituted with one or more methyl, methoxyl, halogen,
trifluoromethyl, or methoxycarbonyl groups;
[0372] R.sub.5 is --H, a C.sub.1-C.sub.12 straight chain alkyl,
i-C.sub.3H.sub.7, or --C.sub.6H.sub.5;
[0373] R.sub.6 is --H, a C.sub.1-C.sub.12 straight chain alkyl,
i-C.sub.3H.sub.7, C.sub.3-C.sub.7 cycloalkyl, or
--C.sub.6H.sub.5.
[0374] The compounds of Formula (III) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. The compounds of Formula (III) or a pharmaceutically
acceptable salt thereof are also useful for inhibiting the growth
of a cancer cell or neoplastic cell. The compounds of Formula (III)
or a pharmaceutically acceptable salt thereof are useful for
treating or preventing a viral infection in a patient in need of
such treatment or prevention. The compounds of Formula (III) or a
pharmaceutically acceptable salt thereof are also useful for
inhibiting the replication or infectivity of a virus. The compounds
of Formula (III) or a pharmaceutically acceptable salt thereof are
also useful for causing immunosuppression in a patient in need
thereof. The compounds of Formula (III) or a pharmaceutically
acceptable salt thereof are also useful for treating an autoimmune
disease in a patient in need of such treatment or prevention.
[0375] A preferred subclass of the compounds of Formula (III) is
that wherein:
[0376] R.sub.1 is --H;
[0377] R.sub.2 is --CH.sub.3, --CH.sub.2C.sub.6H.sub.5;
[0378] R.sub.3 is --CH.sub.3;
[0379] R.sub.4 is --H or a C.sub.1-C.sub.15 straight chain
alkyl;
[0380] R.sub.5 is --H or a C.sub.1-C.sub.5 straight chain alkyl;
and
[0381] R.sub.6 is --H or --CH.sub.3;
[0382] A more preferred subclass of the compounds of Formula (III)
is that wherein:
[0383] R.sub.1 is --H;
[0384] R.sub.2 and R.sub.3 is --CH.sub.3;
[0385] R.sub.4 is --H or --(CH.sub.2).sub.14CH.sub.3;
[0386] R.sub.5 is --H or -n-C.sub.5H.sub.11; and
[0387] R.sub.6 is --H.
[0388] The present invention also provides compositions comprising
a pharmaceutically acceptable carrier and an effective amount of a
compound of Formula (III) or a pharmaceutically acceptable salt
thereof, wherein, in the compound of Formula (III):
[0389] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, and --C(O)OCH.sub.2C.sub.6H.sub.5;
[0390] R.sub.2 is a C.sub.1-C.sub.10 straight chain alky or
--CH.sub.2C.sub.6H.sub.5, the --CH.sub.2C.sub.6H.sub.5 being
unsubstituted or substituted on the phenyl with one or more
methoxyl, halogen, methyl, nitro, trifluoromethyl, or
methoxylcarbonyl groups;
[0391] R.sub.3 is --CH.sub.3, --CH.sub.2CH.sub.3, or
--C.sub.6H.sub.5;
[0392] R.sub.4 is --H, a C.sub.1-C.sub.15 straight chain alkyl,
-2-pyrrolyl, -3-pyrrolyl, -2-furanyl, -3-furanyl, or
--C.sub.6H.sub.5, the --C.sub.6H.sub.5 being unsubstituted or
substituted with one or more methyl, methoxyl, halogen,
trifluoromethyl, or methoxycarbonyl groups;
[0393] R.sub.5 is --H, a C.sub.1-C.sub.12 straight chain alkyl,
i-C.sub.3H.sub.7, or --C.sub.6H.sub.5;
[0394] R.sub.6 is --H, a C.sub.1-C.sub.12 straight chain alkyl,
i-C.sub.3H.sub.7, C.sub.3-C.sub.7 cycloalkyl, or
--C.sub.6H.sub.5.
[0395] The compositions comprising a pharmaceutically acceptable
carrier and a compound of Formula (III) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. These compositions are also useful for inhibiting
the growth of a cancer cell or neoplastic cell. The compositions
comprising a pharmaceutically acceptable carrier and a compound of
Formula (III) or a pharmaceutically acceptable salt thereof are
useful for treating or preventing a viral infection in a patient in
need of such treatment or prevention. These compositions are also
useful for inhibiting the replication or infectivity of a virus.
The compositions comprising a pharmaceutically acceptable carrier
and a compound of Formula (III) or a pharmaceutically acceptable
salt thereof are also useful for causing immunosuppression in a
patient in need thereof. The compositions comprising a
pharmaceutically acceptable carrier and a compound of Formula (III)
or a pharmaceutically acceptable salt thereof are also useful for
treating an autoimmune disease in a patient in need of such
treatment or prevention.
[0396] A preferred subclass of the compositions comprising a
pharmaceutically acceptable carrier and a compound of Formula (III)
or a pharmaceutically acceptable salt thereof is that wherein, in
the compound of Formula (III):
[0397] R.sub.1 is --H;
[0398] R.sub.2 is --CH.sub.3, --CH.sub.2C.sub.6H.sub.5;
[0399] R.sub.3 is --CH.sub.3;
[0400] R.sub.4 is --H or a C.sub.1-C.sub.15 straight chain
alkyl;
[0401] R.sub.5 is --H or a C.sub.1-C.sub.5 straight chain alkyl;
and
[0402] R.sub.6 is --H or --CH.sub.3.
[0403] A more preferred subclass of the compositions comprising a
pharmaceutically acceptable carrier and a compound of Formula (III)
or a pharmaceutically acceptable salt thereof is that wherein, in
the compound of Formula (III):
[0404] R.sub.1 is --H;
[0405] R.sub.2 and R.sub.3 is --CH.sub.3;
[0406] R.sub.4 is --H or --(CH.sub.2).sub.14CH.sub.3;
[0407] R.sub.5 is -n-C.sub.5H.sub.11; and
[0408] R.sub.6is --H.
[0409] The invention further provides methods for treating or
preventing cancer or neoplastic disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (III) or a
pharmaceutically acceptable salt thereof, wherein, in the compound
of Formula (III):
[0410] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, and --C(O)OCH.sub.2C.sub.6H.sub.5;
[0411] R.sub.2 is a C.sub.1-C.sub.10 straight chain alky or
--CH.sub.2C.sub.6H.sub.5, the --CH.sub.2C.sub.6H.sub.5 being
unsubstituted or substituted on the phenyl with one or more
methoxyl, halogen, methyl, nitro, trifluoromethyl, or
methoxylcarbonyl groups;
[0412] R.sub.3 is --CH.sub.3, --CH.sub.2CH.sub.3, or
--C.sub.6H.sub.5;
[0413] R.sub.4 is a C.sub.1-C.sub.15 straight chain alkyl,
-2-pyrrolyl, -3-pyrrolyl, -2-furanyl, -3-furanyl, or
--C.sub.6H.sub.5, the --C.sub.6H.sub.5 being unsubstituted or
substituted with one or more methyl, methoxyl, halogen,
trifluoromethyl, or methoxycarbonyl groups;
[0414] R.sub.5 is --H, a C.sub.1-C.sub.12 straight chain alkyl,
i-C.sub.3H.sub.7, or --C.sub.6H.sub.5;
[0415] R.sub.6 is --H, a C.sub.1-C.sub.12 straight chain alkyl,
i-C.sub.3H.sub.7, C.sub.3-C.sub.7 cycloalkyl, or
--C.sub.6H.sub.5.
[0416] For use in the methods for treating or preventing cancer or
neoplastic disease, a preferred subclass of the compounds of
Formula (III) is that wherein, in the compound of Formula
(III):
[0417] R.sub.1 is --H;
[0418] R.sub.2 is --CH.sub.3, --CH.sub.2C.sub.6H.sub.5;
[0419] R.sub.3 is --CH.sub.3;
[0420] R.sub.4 is --H or a C.sub.1-C.sub.15 straight chain
alkyl;
[0421] R.sub.5 is --H or a C.sub.1-C.sub.5 straight chain alkyl;
and
[0422] R.sub.6 is --H or --CH.sub.3.
[0423] For use in the methods for treating or preventing cancer or
neoplastic disease, a more preferred subclass of the compounds of
Formula (III) is that wherein, in the compound of Formula
(III):
[0424] R.sub.1 is --H;
[0425] R.sub.2 and R.sub.3 is --CH.sub.3;
[0426] R.sub.4 is --H or --(CH.sub.2).sub.14CH.sub.3;
[0427] R.sub.5 is --H or -n-C.sub.5H.sub.11; and
[0428] R.sub.6 is --H.
[0429] The invention further provides methods for inhibiting the
growth of a cancer cell or neoplastic cell comprising contacting a
cancer cell or neoplastic cell with an effective amount of a
compound having the general Formula (III) or a pharmaceutically
acceptable salt thereof, wherein, in the compound of Formula
(III):
[0430] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, and --C(O)OCH.sub.2C.sub.6H.sub.5;
[0431] R.sub.2 is a C.sub.1-C.sub.10 straight chain alky or
--CH.sub.2C.sub.6H.sub.5, the --CH.sub.2C.sub.6H.sub.5 being
unsubstituted or substituted on the phenyl with one or more
methoxyl, halogen, methyl, nitro, trifluoromethyl, or
methoxylcarbonyl groups;
[0432] R.sub.3 is --CH.sub.3, --CH.sub.2CH.sub.3, or
--C.sub.6H.sub.5;
[0433] R.sub.4 is a C.sub.1-C.sub.15 straight chain alkyl,
-2-pyrrolyl, -3-pyrrolyl, -2-furanyl, -3-furanyl, or
--C.sub.6H.sub.5, the --C.sub.6H.sub.5 being unsubstituted or
substituted with one or more methyl, methoxyl, halogen,
trifluoromethyl, or methoxycarbonyl groups,
[0434] R.sub.5 is --H, a C.sub.1-C.sub.12 straight chain alkyl,
i-C.sub.3H.sub.7, or --C.sub.6H.sub.5;
[0435] R.sub.6 is --H, a C.sub.1-C.sub.12 straight chain alkyl,
i-C.sub.3H.sub.7, C.sub.3-C.sub.7 cycloalkyl, or
--C.sub.6H.sub.5.
[0436] For use in the methods for inhibiting the growth of a cancer
or neoplastic cell, a preferred subclass of the compounds of
Formula (III) is that wherein, in the compound of Formula
(III):
[0437] R.sub.1 is --H;
[0438] R.sub.2 is --CH.sub.3, --CH.sub.2C.sub.6H.sub.5;
[0439] R.sub.3 is --CH.sub.3;
[0440] R.sub.4 is --H or a C.sub.1-C.sub.15 straight chain
alkyl;
[0441] R.sub.5 is --H or a C.sub.1-C.sub.5 straight chain alkyl;
and
[0442] R.sub.6 is --H or --CH.sub.3.
[0443] For use in the methods for inhibiting the growth of a cancer
or neoplastic cell, a more preferred subclass of the compounds of
Formula (III) is that wherein, in the compound of Formula
(III):
[0444] R.sub.1 is --H;
[0445] R.sub.2 and R.sub.3 is --CH.sub.3;
[0446] R.sub.4is --H or --(CH.sub.2).sub.14CH.sub.3;
[0447] R.sub.5is --H or -n-C.sub.5H.sub.11; and
[0448] R.sub.6is --H.
[0449] The invention further provides methods for treating or
preventing a viral infection in a patient comprising administering
to a patient in need of such treatment or prevention an effective
amount of a compound of Formula (III) or a pharmaceutically
acceptable salt thereof, wherein, in the compound of Formula
(III):
[0450] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, and --C(O)OCH.sub.2C.sub.6H.sub.5;
[0451] R.sub.2 is a C.sub.1-C.sub.10 straight chain alky or
--CH.sub.2C.sub.6H.sub.5, the --CH.sub.2C.sub.6H.sub.5 being
unsubstituted or substituted on the phenyl with one or more
methoxyl, halogen, methyl, nitro, trifluoromethyl, or
methoxylcarbonyl groups;
[0452] R.sub.3 is --CH.sub.3, --CH.sub.2CH.sub.3, or
--C.sub.6H.sub.5;
[0453] R.sub.4 is a C.sub.1-C.sub.15 straight chain alkyl,
-2-pyrrolyl, -3-pyrrolyl, -2-furanyl, -3-furanyl, or
--C.sub.6H.sub.5, the --C.sub.6H.sub.5 being unsubstituted or
substituted with one or more methyl, methoxyl, halogen,
trifluoromethyl, or methoxycarbonyl groups;
[0454] R.sub.5 is --H, a C.sub.1-C.sub.12 straight chain alkyl,
i-C.sub.3H.sub.7, or --C.sub.6H.sub.5;
[0455] R.sub.6 is --H, a C.sub.1-C.sub.12 straight chain alkyl,
i-C.sub.3H.sub.7, C.sub.3-C.sub.7 cycloalkyl, or
--C.sub.6H.sub.5.
[0456] For use in the present methods for treating or preventing a
viral infection, a preferred subclass of the compounds of Formula
(III) is that wherein, in the compound of Formula (III):
[0457] R.sub.1 is --H;
[0458] R.sub.2 is --CH.sub.3, --CH.sub.2C.sub.6H.sub.5;
[0459] R.sub.3 is --CH.sub.3;
[0460] R.sub.4 is --H or a C.sub.1-C.sub.15 straight chain
alkyl;
[0461] R.sub.5 is --H or a C.sub.1-C.sub.15 straight chain alkyl;
and
[0462] R.sub.6 is --H or --CH.sub.3.
[0463] For use in the present methods for treating or preventing a
viral infection, a more preferred subclass of the compounds of
Formula (III) is that wherein, in the compound of Formula
(III):
[0464] R.sub.1 is --H;
[0465] R.sub.2 and R.sub.3 is --CH.sub.3;
[0466] R.sub.4 is --H or --(CH.sub.2).sub.14CH.sub.3;
[0467] R.sub.5 is --H or -n-C.sub.5H.sub.11; and
[0468] R.sub.6 is --H.
[0469] The invention further provides methods for inhibiting the
replication or infectivity of a virus comprising contacting a virus
or a virus-infected cell with an effective amount of a compound
having the general Formula (III) or a pharmaceutically acceptable
salt thereof, wherein, in the compound of Formula (III):
[0470] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, and --C(O)OCH.sub.2C.sub.6H.sub.5;
[0471] R.sub.2 is a C.sub.1-C.sub.10 straight chain alky or
--CH.sub.2C.sub.6H.sub.5, the --CH.sub.2C.sub.6H.sub.5 being
unsubstituted or substituted on the phenyl with one or more
methoxyl, halogen, methyl, nitro, trifluoromethyl, or
methoxylcarbonyl groups;
[0472] R.sub.3 is --CH.sub.3, --CH.sub.2CH.sub.3, or
--C.sub.6H.sub.5;
[0473] R.sub.4 is a C.sub.1-C.sub.15 straight chain alkyl,
-2-pyrrolyl, -3-pyrrolyl, -2-furanyl, -3-furanyl, or
--C.sub.6H.sub.5, the --C.sub.6H.sub.5 being unsubstituted or
substituted with one or more methyl, methoxyl, halogen,
trifluoromethyl, or methoxycarbonyl groups;
[0474] R.sub.5 is --H, a C.sub.1-C.sub.12 straight chain alkyl,
i-C.sub.3H.sub.7, or --C.sub.6H.sub.5;
[0475] R.sub.6 is --H, a C.sub.1-C.sub.12 straight chain alkyl,
i-C.sub.3H.sub.7, C.sub.3-C.sub.7 cycloalkyl, or
--C.sub.6H.sub.5.
[0476] For use in the methods for inhibiting the replication or
infectivity of a virus, a preferred subclass of the compounds of
Formula (III) are those wherein:
[0477] R.sub.1 is --H;
[0478] R.sub.2 is --CH.sub.3, --CH.sub.2C.sub.6H.sub.5;
[0479] R.sub.3 is --CH.sub.3;
[0480] R.sub.4 is --H or a C.sub.1-C.sub.15 straight chain
alkyl;
[0481] R.sub.5 is --H or a C.sub.1-C.sub.15 straight chain alkyl;
and
[0482] R.sub.6 is --H or --CH.sub.3.
[0483] For use in the methods for inhibiting the replication or
infectivity of a virus, a more preferred subclass of the compounds
of Formula (III) are those wherein:
[0484] R,is --H;
[0485] R.sub.2 and R.sub.3 is --CH.sub.3;
[0486] R.sub.4 is --H or --(CH.sub.2).sub.14CH.sub.3;
[0487] R.sub.5 is --H or -n-C.sub.5H.sub.11; and
[0488] R.sub.6 is --H.
[0489] The invention further provides methods for causing
immunosuppression in a patient comprising administering to a
patient in need thereof an effective amount of a compound of
Formula (III) or a pharmaceutically acceptable salt thereof,
wherein, in the compound of Formula (III):
[0490] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, and --C(O)OCH.sub.2C.sub.6H.sub.5;
[0491] R.sub.2 is a C.sub.1-C.sub.10 straight chain alky or
--CH.sub.2C.sub.6H.sub.5, the --CH.sub.2C.sub.6H.sub.5 being
unsubstituted or substituted on the phenyl with one or more
methoxyl, halogen, methyl, nitro, trifluoromethyl, or
methoxylcarbonyl groups;
[0492] R.sub.3 is --CH.sub.3, --CH.sub.2CH.sub.3, or
--C.sub.6H.sub.5;
[0493] R.sub.4 is a C.sub.1-C.sub.15 straight chain alkyl,
-2-pyrrolyl, -3-pyrrolyl, -2-furanyl, -3-furanyl, or
--C.sub.6H.sub.5, the --C.sub.6H.sub.5 being unsubstituted or
substituted with one or more methyl, methoxyl, halogen,
trifluoromethyl, or methoxycarbonyl groups;
[0494] R.sub.5 is --H, a C.sub.1-C.sub.12 straight chain alkyl,
i-C.sub.3H.sub.7, or --C.sub.6H.sub.5;
[0495] R.sub.6 is --H, a C.sub.1-C.sub.12 straight chain alkyl,
i-C.sub.3H.sub.7, C.sub.3-C.sub.7 cycloalkyl, or
--C.sub.6H.sub.5.
[0496] For use in the methods for causing immunosuppression, a
preferred subclass of the compounds of Formula (III) are those
wherein:
[0497] R.sub.1 is --H;
[0498] R.sub.2 is --CH.sub.3, --CH.sub.2C.sub.6H.sub.5;
[0499] R.sub.3 is --CH.sub.3;
[0500] R.sub.4 is --H or a C.sub.1-C.sub.15 straight chain
alkyl;
[0501] R.sub.5 is --H or a C.sub.1-C.sub.5 straight chain alkyl;
and
[0502] R.sub.6 is --H or --CH.sub.3.
[0503] For use in the methods for causing immunosuppression, a more
preferred subclass of the compounds of Formula (III) are those
wherein:
[0504] R.sub.1 is --H;
[0505] R.sub.2 and R.sub.3 is --CH.sub.3;
[0506] R.sub.4 is --H or --(CH.sub.2).sub.14CH.sub.3;
[0507] R.sub.5 is --H or -n-C.sub.5H.sub.11; and
[0508] R.sub.6 is --H.
[0509] The invention further provides methods for treating or
preventing an autoimmune disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (III) or a
pharmaceutically acceptable salt thereof, wherein, in the compound
of Formula (III):
[0510] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, and --C(O)OCH.sub.2C.sub.6H.sub.5;
[0511] R.sub.2 is a C.sub.1-C.sub.10 straight chain alky or
--CH.sub.2C.sub.6H.sub.5, the --CH.sub.2C.sub.6H.sub.5 being
unsubstituted or substituted on the phenyl with one or more
methoxyl, halogen, methyl, nitro, trifluoromethyl, or
methoxylcarbonyl groups;
[0512] R.sub.3 is --CH.sub.3, --CH.sub.2CH.sub.3, or
--C.sub.6H.sub.5;
[0513] R.sub.4 is a C.sub.1-C.sub.15 straight chain alkyl,
-2-pyrrolyl, -3-pyrrolyl, -2-furanyl, -3-furanyl, or
--C.sub.6H.sub.5, the --C.sub.6H.sub.5 being unsubstituted or
substituted with one or more methyl, methoxyl, halogen,
trifluoromethyl, or methoxycarbonyl groups;
[0514] R.sub.5 is --H, a C.sub.1-C.sub.12 straight chain alkyl,
i-C.sub.3H.sub.7, or --C.sub.6H.sub.5;
[0515] R.sub.6 is --H, a C.sub.1-C.sub.12 straight chain alkyl,
i-C.sub.3H.sub.7, C.sub.3-C.sub.7 cycloalkyl, or
--C.sub.6H.sub.5.
[0516] For use in the methods for treating or preventing an
autoimmune disease, a preferred subclass of the compounds of
Formula (III) are those wherein:
[0517] R.sub.1 is --H;
[0518] R.sub.2 is --CH.sub.3, --CH.sub.2C.sub.6H.sub.5;
[0519] R.sub.3 is --CH.sub.3;
[0520] R.sub.4 is --H or a C.sub.1-C.sub.15 straight chain
alkyl;
[0521] R.sub.5 is --H or a C.sub.1-C.sub.5 straight chain alkyl;
and
[0522] R.sub.6 is --H or --CH.sub.3.
[0523] For use in the methods for treating or preventing an
autoimmune disease, a more preferred subclass of the compounds of
Formula (III) are those wherein:
[0524] R.sub.1 is --H;
[0525] R.sub.2 and R.sub.3 is --CH.sub.3,
[0526] R.sub.4 is --H or --(CH.sub.2).sub.14CH.sub.3;
[0527] R.sub.5 is --H or -n-C.sub.5H.sub.11; and
[0528] R.sub.6is --H.
5.4. Formula IV
[0529] The present invention encompasses novel compounds having the
general Formula (IV) and pharmaceutically acceptable salts thereof,
wherein:
[0530] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, and --C(O)OCH.sub.2C.sub.6H.sub.5;
[0531] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl, or
--CH.sub.2C.sub.6H.sub.5, the --CH.sub.2C.sub.6H.sub.5 being
unsubstituted or substituted on the phenyl with one or more
methoxyl, halogen, methyl, nitro, trifluoromethyl, or
methoxylcarbonyl groups;
[0532] R.sub.3 is --CH.sub.3, --CH.sub.2CH.sub.3, or
--C.sub.6H.sub.5;
[0533] R.sub.4 is a C.sub.1-C.sub.15 straight chain alkyl,
-2-pyrrolyl, -3-pyrrolyl, -2-furanyl, -3-furanyl, or
--C.sub.6H.sub.5, the --C.sub.6H.sub.5 being unsubstituted or
substituted with one or more methyl, methoxyl, halogen,
trifluoromethyl, or methoxycarbonyl groups;
[0534] R.sub.8 is --H, --CH.sub.3, --CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.3, or --(CH.sub.2).sub.3CH.sub.3; and
[0535] m is 1 to 4.
[0536] The compounds of Formula (IV) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. The compounds of Formula (IV) or a pharmaceutically
acceptable salt thereof are also useful for inhibiting the growth
of a cancer cell or neoplastic cell. The compounds of Formula (IV)
or a pharmaceutically acceptable salt thereof are useful for
treating or preventing a viral infection in a patient in need of
such treatment or prevention. The compounds of Formula (IV) or a
pharmaceutically acceptable salt thereof are also useful for
inhibiting the replication or infectivity of a virus. The compounds
of Formula (IV) or a pharmaceutically acceptable salt thereof are
also useful for causing immunosuppression in a patient in need
thereof. The compounds of Formula (IV) or a pharmaceutically
acceptable salt thereof are also useful for treating an autoimmune
disease in a patient in need of such treatment or prevention.
[0537] A preferred subclass of the compounds of Formula (IV) is
that wherein:
[0538] R.sub.1 is --H;
[0539] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5;
[0540] R.sub.3 is --CH.sub.3;
[0541] R.sub.4 is --H or a C.sub.1-C.sub.15 straight chain
alkyl;
[0542] R.sub.8 is --H or --CH.sub.3; and
[0543] m is 2.
[0544] A more preferred subclass of the compounds of Formula (IV)
is that wherein:
[0545] R.sub.1 is --H;
[0546] R.sub.2, R.sub.3, and R.sub.4 is --CH.sub.3;
[0547] R.sub.8 is --H or CH.sub.3; and
[0548] m is 2.
[0549] The present invention also provides compositions comprising
a pharmaceutically acceptable carrier and an effective amount of a
compound of Formula (IV) or a pharmaceutically acceptable salt
thereof, wherein, in the compound of Formula (IV):
[0550] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, and --C(O)OCH.sub.2C.sub.6H.sub.5;
[0551] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl, or
--CH.sub.2C.sub.6H.sub.5, the --CH.sub.2C.sub.6H.sub.5 being
unsubstituted or substituted on the phenyl with one or more
methoxyl, halogen, methyl, nitro, trifluoromethyl, or
methoxylcarbonyl groups;
[0552] R.sub.3 is --CH.sub.3, --CH.sub.2CH.sub.3, or
--C.sub.6H.sub.5;
[0553] R.sub.4 is a C.sub.1-C.sub.15 straight chain alkyl,
-2-pyrrolyl, -3-pyrrolyl, -2-furanyl, -3-furanyl, or
--C.sub.6H.sub.5, the --C.sub.6H.sub.5 being unsubstituted or
substituted with one or more methyl, methoxyl, halogen,
trifluoromethyl, or methoxycarbonyl groups;
[0554] R.sub.8 is --H, --CH.sub.3, --CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.3, or --(CH.sub.2).sub.3CH.sub.3; and
[0555] m is 1 to 4.
[0556] The compositions comprising a pharmaceutically acceptable
carrier and a compound of Formula (IV) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. These compositions are also useful for inhibiting
the growth of a cancer cell or neoplastic cell. The compositions
comprising a pharmaceutically acceptable carrier and a compound of
Formula (IV) or a pharmaceutically acceptable salt thereof are
useful for treating or preventing a viral infection in a patient in
need of such treatment or prevention. These compositions are also
useful for inhibiting the replication or infectivity of a virus.
The compositions comprising a pharmaceutically acceptable carrier
and a compound of Formula (IV) or a pharmaceutically acceptable
salt thereof are also useful for causing immunosuppression in a
patient in need thereof. The compositions comprising a
pharmaceutically acceptable carrier and a compound of Formula (IV)
or a pharmaceutically acceptable salt thereof are also useful for
treating an autoimmune disease in a patient in need of such
treatment or prevention.
[0557] A preferred subclass of the compositions comprising a
pharmaceutically acceptable carrier and a compound of Formula (IV)
or a pharmaceutically acceptable salt thereof is that wherein, in
the compound of Formula (IV):
[0558] R.sub.1 is --H;
[0559] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5;
[0560] R.sub.3 is --CH.sub.3;
[0561] R.sub.4 is --H or a C.sub.1-C.sub.15 straight chain
alkyl;
[0562] R.sub.8 is --H or --CH.sub.3; and
[0563] m is 2.
[0564] A more preferred subclass of the compositions comprising a
pharmaceutically acceptable carrier and a compound of Formula (IV)
or a pharmaceutically acceptable salt thereof is that wherein, in
the compound of Formula (IV):
[0565] R.sub.1 is --H;
[0566] R.sub.2, R.sub.3, and R.sub.4 is --CH.sub.3;
[0567] R.sub.8 is --H or CH.sub.3; and
[0568] m is 2.
[0569] The invention further provides methods for treating or
preventing cancer or neoplastic disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (IV) or a
pharmaceutically acceptable salt thereof, wherein, in the compound
of Formula (IV):
[0570] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, and --C(O)OCH.sub.2C.sub.6H.sub.5;
[0571] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl, or
--CH.sub.2C.sub.6H.sub.5 the --CH.sub.2C.sub.6H.sub.5 being
unsubstituted or substituted on the phenyl with one or more
methoxyl, halogen, methyl, nitro, trifluoromethyl, or
methoxylcarbonyl groups;
[0572] R.sub.3 is --CH.sub.3, --CH.sub.2CH.sub.3, or
--C.sub.6H.sub.5;
[0573] R.sub.4 is a C.sub.1-C.sub.15 straight chain alkyl,
-2-pyrrolyl, -3-pyrrolyl, -2-furanyl, -3-furanyl, or
--C.sub.6H.sub.5, the --C.sub.6H.sub.5 being unsubstituted or
substituted with one or more methyl, methoxyl, halogen,
trifluoromethyl, or methoxycarbonyl groups;
[0574] R.sub.8 is --H, --CH.sub.3, --CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.3, or --(CH.sub.2).sub.3CH.sub.3; and
[0575] m is 1 to 4.
[0576] For use in the methods for treating or preventing cancer or
neoplastic disease, a preferred subclass of the compounds of
Formula (IV) is that wherein, in the compound of Formula (IV):
[0577] R.sub.1 is --H;
[0578] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5;
[0579] R.sub.3 is --CH.sub.3;
[0580] R.sub.4 is --H or a C.sub.1-C.sub.15 straight chain
alkyl;
[0581] R.sub.8 is --H or --CH.sub.3; and
[0582] m is 2.
[0583] For use in the methods for treating or preventing cancer or
neoplastic disease, a more preferred subclass of the compounds of
Formula (IV) is that wherein, in the compound of Formula (IV):
[0584] R.sub.1 is --H;
[0585] R.sub.2, R.sub.3, and R.sub.4 is --CH.sub.3;
[0586] R.sub.8 is --H or CH.sub.3; and
[0587] m is 2.
[0588] The invention further provides methods for inhibiting the
growth of a cancer cell or neoplastic cell comprising contacting a
cancer cell or neoplastic cell with an effective amount of a
compound having the general Formula (IV) or a pharmaceutically
acceptable salt thereof, wherein, in the compound of Formula
(IV):
[0589] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, and --C(O)OCH.sub.2C.sub.6H.sub.5;
[0590] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl, or
--CH.sub.2C.sub.6H.sub.5, the --CH.sub.2C.sub.6H.sub.5 being
unsubstituted or substituted on the phenyl with one or more
methoxyl, halogen, methyl, nitro, trifluoromethyl, or
methoxylcarbonyl groups;
[0591] R.sub.3 is --CH.sub.3, --CH.sub.2CH.sub.3, or
--C.sub.6H.sub.5;
[0592] R.sub.4 is a C.sub.1-C.sub.15 straight chain alkyl,
-2-pyrrolyl, -3-pyrrolyl, -2-furanyl, -3-furanyl, or
--C.sub.6H.sub.5, the --C.sub.6H.sub.5 being unsubstituted or
substituted with one or more methyl, methoxyl, halogen,
trifluoromethyl, or methoxycarbonyl groups,
[0593] R.sub.8 is --H, --CH.sub.3, --CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.3, or --(CH.sub.2).sub.3CH.sub.3; and
[0594] m is 1 to 4.
[0595] For use in the methods for inhibiting the growth of a cancer
or neoplastic cell, a preferred subclass of the compounds of
Formula (IV) is that wherein, in the compound of Formula (IV):
[0596] R.sub.1 is --H;
[0597] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5;
[0598] R.sub.3 is --CH.sub.3;
[0599] R.sub.4 is --H or a C.sub.1-C.sub.15 straight chain
alkyl;
[0600] R.sub.8 is --H or --CH.sub.3; and
[0601] m is 2.
[0602] For use in the methods for inhibiting the growth of a cancer
or neoplastic cell, a more preferred subclass of the compounds of
Formula (IV) is that wherein, in the compound of Formula (IV):
[0603] R.sub.1 is --H;
[0604] R.sub.2, R.sub.3, and R.sub.4 is --CH.sub.3;
[0605] R.sub.8 is --H or CH.sub.3; and
[0606] m is 2.
[0607] The invention further provides methods for treating or
preventing a viral infection in a patient comprising administering
to a patient in need of such treatment or prevention an effective
amount of a compound of Formula (IV) or a pharmaceutically
acceptable salt thereof, wherein, in the compound of Formula
(IV):
[0608] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, and --C(O)OCH.sub.2C.sub.6H.sub.5;
[0609] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl, or
--CH.sub.2C.sub.6H.sub.5, the --CH.sub.2C.sub.6H.sub.5 being
unsubstituted or substituted on the phenyl with one or more
methoxyl, halogen, methyl, nitro, trifluoromethyl, or
methoxylcarbonyl groups;
[0610] R.sub.3 is --CH.sub.3, --CH.sub.2CH.sub.3, or
--C.sub.6H.sub.5;
[0611] R.sub.4 is a C.sub.1-C.sub.15 straight chain alkyl,
-2-pyrrolyl, -3-pyrrolyl, -2-furanyl, -3-furanyl, or
--C.sub.6H.sub.5, the --C.sub.6H.sub.5 being unsubstituted or
substituted with one or more methyl, methoxyl, halogen,
trifluoromethyl, or methoxycarbonyl groups;
[0612] R.sub.8 is --H, --CH.sub.3, --CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.3, or --(CH.sub.2).sub.3CH.sub.3; and
[0613] m is 1 to 4.
[0614] For use in the present methods for treating or preventing a
viral infection, a preferred subclass of the compounds of Formula
(IV) is that wherein, in the compound of Formula (IV):
[0615] R.sub.1 is --H;
[0616] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5;
[0617] R.sub.3 is --CH.sub.3;
[0618] R.sub.4 is --H or a C.sub.1-C.sub.15 straight chain
alkyl;
[0619] R.sub.5 is --H or --CH.sub.3; and
[0620] m is 2.
[0621] For use in the present methods for treating or preventing a
viral infection, a more preferred subclass of the compounds of
Formula (IV) is that wherein, in the compound of Formula (IV):
[0622] R.sub.1 is --H;
[0623] R.sub.2, R.sub.3, and R.sub.4 is --CH.sub.3;
[0624] R.sub.8 is --H or CH.sub.3; and
[0625] m is 2.
[0626] The invention further provides methods for inhibiting the
replication or infectivity of a virus comprising contacting a virus
or a virus-infected cell with an effective amount of a compound
having the general Formula (IV) or a pharmaceutically acceptable
salt thereof, wherein, in the compound of Formula (IV):
[0627] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, and --C(O)OCH.sub.2C.sub.6H.sub.5;
[0628] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl, or
--CH.sub.2C.sub.6H.sub.5, the --CH.sub.2C.sub.6H.sub.5 being
unsubstituted or substituted on the phenyl with one or more
methoxyl, halogen, methyl, nitro, trifluoromethyl, or
methoxylcarbonyl groups;
[0629] R.sub.3 is --CH.sub.3, --CH.sub.2CH.sub.3, or
--C.sub.6H.sub.5;
[0630] R.sub.4 is a C.sub.1-C.sub.15 straight chain alkyl,
-2-pyrrolyl, -3-pyrrolyl, -2-furanyl, -3-furanyl, or
--C.sub.6H.sub.5, the --C.sub.6H.sub.5 being unsubstituted or
substituted with one or more methyl, methoxyl, halogen,
trifluoromethyl, or methoxycarbonyl groups;
[0631] R.sub.8 is --H, --CH.sub.3, --CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.3, or --(CH.sub.2).sub.3CH.sub.3; and
[0632] m is 1 to 4.
[0633] For use in the methods for inhibiting the replication or
infectivity of a virus, a preferred subclass of the compounds of
Formula (IV) are those wherein:
[0634] R.sub.1 is --H;
[0635] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5;
[0636] R.sub.3 is --CH.sub.3;
[0637] R.sub.4 is --H or a C.sub.1-C.sub.15 straight chain
alkyl;
[0638] R.sub.8 is --H or --CH.sub.3; and
[0639] m is 2.
[0640] For use in the methods for inhibiting the replication or
infectivity of a virus, a more preferred subclass of the compounds
of Formula (IV) are those wherein:
[0641] R.sub.1 is --H;
[0642] R.sub.2, R.sub.3, and R.sub.4 is --CH.sub.3;
[0643] R.sub.8 is --H or CH.sub.3; and
[0644] m is 2.
[0645] The invention further provides methods for causing
immunosuppression in a patient comprising administering to a
patient in need thereof an effective amount of a compound of
Formula (IV) or a pharmaceutically acceptable salt thereof,
wherein, in the compound of Formula (IV):
[0646] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, and --C(O)OCH.sub.2C.sub.6H.sub.5;
[0647] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl, or
--CH.sub.2C.sub.6H.sub.5, the --CH.sub.2C.sub.6H.sub.5 being
unsubstituted or substituted on the phenyl with one or more
methoxyl, halogen, methyl, nitro, trifluoromethyl, or
methoxylcarbonyl groups;
[0648] R.sub.3 is --CH.sub.3, --CH.sub.2CH.sub.3, or
--C.sub.6H.sub.5;
[0649] R.sub.4 is a C.sub.1-C.sub.15 straight chain alkyl,
-2-pyrrolyl, -3-pyrrolyl, -2-furanyl, -3-furanyl, or
--C.sub.6H.sub.5, the --C.sub.6H.sub.5 being unsubstituted or
substituted with one or more methyl, methoxyl, halogen,
trifluoromethyl, or methoxycarbonyl groups;
[0650] R.sub.8 is --H, --CH.sub.3, --CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.3, or --(CH.sub.2).sub.3CH.sub.3; and
[0651] m is 1 to 4.
[0652] For use in the methods for causing immunosuppression, a
preferred subclass of the compounds of Formula (IV) are those
wherein:
[0653] R.sub.1 is --H;
[0654] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5;
[0655] R.sub.3 is --CH.sub.3;
[0656] R.sub.4 is --H or a C.sub.1-C.sub.15 straight chain
alkyl;
[0657] R.sub.8 is --H or --CH.sub.3; and
[0658] m is 2.
[0659] For use in the methods for causing immunosuppression, a more
preferred subclass of the compounds of Formula (IV) are those
wherein:
[0660] R.sub.1 is --H;
[0661] R.sub.2, R.sub.3, and R.sub.4 is --CH.sub.3;
[0662] R.sub.8 is --H or CH.sub.3; and
[0663] m is 2.
[0664] The invention further provides methods for treating or
preventing an autoimmune disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (IV) or a
pharmaceutically acceptable salt thereof, wherein, in the compound
of Formula (IV):
[0665] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, and --C(O)OCH.sub.2C.sub.6H.sub.5;
[0666] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl, or
--CH.sub.2C.sub.6H.sub.5, the --CH.sub.2C.sub.6H.sub.5 being
unsubstituted or substituted on the phenyl with one or more
methoxyl, halogen, methyl, nitro, trifluoromethyl, or
methoxylcarbonyl groups;
[0667] R.sub.3 is --CH.sub.3, --CH.sub.2CH.sub.3, or
--C.sub.6H.sub.5;
[0668] R.sub.4 is a C.sub.1-C.sub.15 straight chain alkyl,
-2-pyrrolyl, -3-pyrrolyl, -2-furanyl, -3-furanyl, or
--C.sub.6H.sub.5, the --C.sub.6H.sub.5 being unsubstituted or
substituted with one or more methyl, methoxyl, halogen,
trifluoromethyl, or methoxycarbonyl groups;
[0669] R.sub.8 is --H, --CH.sub.3, --CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.3, or --(CH.sub.2).sub.3CH.sub.3; and
[0670] m is 1 to 4.
[0671] For use in the methods for treating or preventing an
autoimmune disease, a preferred subclass of the compounds of
Formula (IV) are those wherein:
[0672] R.sub.1 is --H;
[0673] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5;
[0674] R.sub.3 is --CH.sub.3;
[0675] R.sub.4 is --H or a C.sub.1-C.sub.15 straight chain
alkyl;
[0676] R.sub.8 is --H or --CH.sub.3; and
[0677] m is 2.
[0678] For use in the methods for treating or preventing an
autoimmune disease, a more preferred subclass of the compounds of
Formula (IV) are those wherein:
[0679] R.sub.1 is --H;
[0680] R.sub.2, R.sub.3, and R.sub.4 is --CH.sub.3;
[0681] R.sub.8 is --H or CH.sub.3; and
[0682] m is 2.
5.5. Formula V
[0683] The present invention encompasses novel compounds having the
general Formula (V) and pharmaceutically acceptable salts thereof,
wherein:
[0684] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, and --C(O)OCH.sub.2C.sub.6H.sub.5;
[0685] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl, or
--CH.sub.2C.sub.6H.sub.5, the --CH.sub.2C.sub.6H.sub.5 being
unsubstituted or substituted on the phenyl with one or more
methoxyl, halogen, methyl, nitro, trifluoromethyl, or
methoxylcarbonyl groups;
[0686] R.sub.3 is --CH.sub.3, --CH.sub.2CH.sub.3, or
--C.sub.6H.sub.5;
[0687] R.sub.7 is --H, a C.sub.1-C.sub.10 straight chain alkyl, or
--CH(CH.sub.3).sub.2; and
[0688] n is 4 to 8.
[0689] The compounds of Formula (V) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. The compounds of Formula (V) or a pharmaceutically
acceptable salt thereof are also useful for inhibiting the growth
of a cancer cell or neoplastic cell. The compounds of Formula (V)
or a pharmaceutically acceptable salt thereof are useful for
treating or preventing a viral infection in a patient in need of
such treatment or prevention. The compounds of Formula (V) or a
pharmaceutically acceptable salt thereof are also useful for
inhibiting the replication or infectivity of a virus. The compounds
of Formula (V) or a pharmaceutically acceptable salt thereof are
also useful for causing immunosuppression in a patient in need
thereof. The compounds of Formula (V) or a pharmaceutically
acceptable salt thereof are also useful for treating-an autoimmune
disease in a patient in need of such treatment or prevention.
[0690] A preferred subclass of the compounds of Formula (V) is that
wherein:
[0691] R.sub.1 is --H;
[0692] R.sub.2 is --CH.sub.3, or --CH.sub.2C.sub.6H.sub.5;
[0693] R.sub.3 is --CH.sub.3;
[0694] R.sub.7 is --H or a C.sub.1-C.sub.4 straight or branched
chain alkyl; and
[0695] n is 4.
[0696] A more preferred subclass of the compounds of Formula (V) is
that wherein:
[0697] R.sub.1 is --H;
[0698] R.sub.2 and R.sub.3 is --CH.sub.3;
[0699] R.sub.7 is --H, --C.sub.2H.sub.5, or -n-C.sub.4H.sub.9;
and
[0700] n is 4.
[0701] The present invention also provides compositions comprising
a pharmaceutically acceptable carrier and an effective amount of a
compound of Formula (V) or a pharmaceutically acceptable salt
thereof, wherein, in the compound of Formula (V):
[0702] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, and --C(O)OCH.sub.2C.sub.6H.sub.5;
[0703] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl, or
--CH.sub.2C.sub.6H.sub.5, the --CH.sub.2C.sub.6H.sub.5 being
unsubstituted or substituted on the phenyl with one or more
methoxyl, halogen, methyl, nitro, trifluoromethyl, or
methoxylcarbonyl groups;
[0704] R.sub.3 is --CH.sub.3, --CH.sub.2CH.sub.3, or
--C.sub.6H.sub.5;
[0705] R.sub.7 is --H, a C.sub.1-C.sub.10 straight chain alkyl, or
--CH(CH.sub.3).sub.2; and
[0706] n is 4 to 8.
[0707] The compositions comprising a pharmaceutically acceptable
carrier and a compound of Formula (V) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. These compositions are also useful for inhibiting
the growth of a cancer cell or neoplastic cell. The compositions
comprising a pharmaceutically acceptable carrier and a compound of
Formula (V) or a pharmaceutically acceptable salt thereof are
useful for treating or preventing a viral infection in a patient in
need of such treatment or prevention. These compositions are also
useful for inhibiting the replication or infectivity of a virus.
The compositions comprising a pharmaceutically acceptable carrier
and a compound of Formula (V) or a pharmaceutically acceptable salt
thereof are also useful for causing immunosuppression in a patient
in need thereof. The compositions comprising a pharmaceutically
acceptable carrier and a compound of Formula (V) or a
pharmaceutically acceptable salt thereof are also useful for
treating an autoimmune disease in a patient in need of such
treatment or prevention.
[0708] A preferred subclass of the compositions comprising a
pharmaceutically acceptable carrier and a compound of Formula (V)
or a pharmaceutically acceptable salt thereof is that wherein, in
the compound of Formula (V):
[0709] R.sub.1 is --H;
[0710] R.sub.2 is --CH.sub.3, or --CH.sub.2C.sub.6H.sub.5;
[0711] R.sub.3 is --CH.sub.3;
[0712] R.sub.7 is --H or a C.sub.1-C.sub.4 straight or branched
chain alkyl; and
[0713] n is 4.
[0714] A more preferred subclass of the compositions comprising a
pharmaceutically acceptable carrier and a compound of Formula (V)
or a pharmaceutically acceptable salt thereof is that wherein, in
the compound of Formula (V):
[0715] R.sub.1 is --H;
[0716] R.sub.2 and R.sub.3 is --CH.sub.3;
[0717] R.sub.7 is --H, --C.sub.2H.sub.5, or -n-C.sub.4H.sub.9;
and
[0718] n is 4.
[0719] The invention further provides methods for treating or
preventing cancer or neoplastic disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (V) or a
pharmaceutically acceptable salt thereof, wherein, in the compound
of Formula (V):
[0720] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, and --C(O)OCH.sub.2C.sub.6H.sub.5;
[0721] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl, or
--CH.sub.2C.sub.6H.sub.5, the --CH.sub.2C.sub.6H.sub.5 being
unsubstituted or substituted on the phenyl with one or more
methoxyl, halogen, methyl, nitro, trifluoromethyl, or
methoxylcarbonyl groups;
[0722] R.sub.3 is --CH.sub.3, --CH.sub.2CH.sub.3, or
--C.sub.6H.sub.5;
[0723] R.sub.7 is --H, a C.sub.1-C.sub.10 straight chain alkyl, or
--CH(CH.sub.3).sub.2; and
[0724] n is 4 to 8.
[0725] For use in the methods for treating or preventing cancer or
neoplastic disease, a preferred subclass of the compounds of
Formula (V) is that wherein, in the compound of Formula (V):
[0726] R.sub.1 is --H;
[0727] R.sub.2 is --CH.sub.3, or --CH.sub.2C.sub.6H.sub.5;
[0728] R.sub.3 is --CH.sub.3;
[0729] R.sub.7 is --H or a C.sub.1-C.sub.4 straight or branched
chain alkyl; and
[0730] n is 4.
[0731] For use in the methods for treating or preventing cancer or
neoplastic disease, a more preferred subclass of the compounds of
Formula (V) is that wherein, in the compound of Formula (V):
[0732] R.sub.1 is --H;
[0733] R.sub.2 and R.sub.3 is --CH.sub.3;
[0734] R.sub.7 is --H, --C.sub.2H.sub.5, or -n-C.sub.4H.sub.9;
and
[0735] n is 4.
[0736] The invention further provides methods for inhibiting the
growth of a cancer cell or neoplastic cell comprising contacting a
cancer cell or neoplastic cell with an effective amount of a
compound having the general Formula (V) or a pharmaceutically
acceptable salt thereof, wherein, in the compound of Formula
(V):
[0737] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, and --C(O)OCH.sub.2C.sub.6H.sub.5;
[0738] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5, the --CH.sub.2C.sub.6H.sub.5 being
unsubstituted or substituted on the phenyl with one or more
methoxyl, halogen, methyl, nitro, trifluoromethyl, or
methoxylcarbonyl groups;
[0739] R.sub.3 is --CH.sub.3, --CH.sub.2CH.sub.3, or
--C.sub.6H.sub.5;
[0740] R.sub.7 is --H, a C.sub.1-C.sub.10 straight chain alkyl, or
--CH(CH.sub.3).sub.2; and
[0741] n is 4 to 8.
[0742] For use in the methods for inhibiting the growth of a cancer
or neoplastic cell, a preferred subclass of the compounds of
Formula (V) is that wherein, in the compound of Formula (V):
[0743] R.sub.1 is --H;
[0744] R.sub.2 is --CH.sub.3, or --CH.sub.2C.sub.6H.sub.5;
[0745] R.sub.3 is --CH.sub.3;
[0746] R.sub.7 is --H or a C.sub.1-C.sub.4 straight or branched
chain alkyl; and
[0747] n is 4.
[0748] For use in the methods for inhibiting the growth of a cancer
or neoplastic cell, a more preferred subclass of the compounds of
Formula (V) is that wherein, in the compound of Formula (V):
[0749] R.sub.1 is --H;
[0750] R.sub.2 and R.sub.3 is --CH.sub.3;
[0751] R.sub.7 is --H, --C.sub.2H.sub.5, or -n-C.sub.4H.sub.9;
and
[0752] n is 4.
[0753] The invention further provides methods for treating or
preventing a viral infection in a patient comprising administering
to a patient in need of such treatment or prevention an effective
amount of a compound of Formula (V) or a pharmaceutically
acceptable salt thereof, wherein, in the compound of Formula
(V):
[0754] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, and --C(O)OCH.sub.2C.sub.6H.sub.5;
[0755] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl, or
--CH.sub.2C.sub.6H.sub.5, the --CH.sub.2C.sub.6H.sub.5 being
unsubstituted or substituted on the phenyl with one or more
methoxyl, halogen, methyl, nitro, trifluoromethyl, or
methoxylcarbonyl groups;
[0756] R.sub.3 is --CH.sub.3, --CH.sub.2CH.sub.3, or
--C.sub.6H.sub.5;
[0757] R.sub.7 is --H, a C.sub.1-C.sub.10 straight chain alkyl, or
--CH(CH.sub.3).sub.2; and
[0758] n is 4 to 8.
[0759] For use in the present methods for treating or preventing a
viral infection, a preferred subclass of the compounds of Formula
(V) is that wherein, in the compound of Formula (V):
[0760] R.sub.1 is --H;
[0761] R.sub.2 is --CH.sub.3, or --CH.sub.2C.sub.6H.sub.5;
[0762] R.sub.3 is --CH.sub.3;
[0763] R.sub.7 is --H or a C.sub.1-C.sub.4 straight or branched
chain alkyl; and
[0764] n is 4.
[0765] For use in the present methods for treating or preventing a
viral infection, a more preferred subclass of the compounds of
Formula (V) is that wherein, in the compound of Formula (V):
[0766] R.sub.1 is --H;
[0767] R.sub.2 and R.sub.3 is --CH.sub.3;
[0768] R.sub.7 is --H, --C.sub.2H.sub.5, or -n-C.sub.4H.sub.9;
and
[0769] n is 4.
[0770] The invention further provides methods for inhibiting the
replication or infectivity of a virus comprising contacting a virus
or a virus-infected cell with an effective amount of a compound
having the general Formula (V) or a pharmaceutically acceptable
salt thereof, wherein, in the compound of Formula (V):
[0771] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, and --C(O)OCH.sub.2C.sub.6H.sub.5;
[0772] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl, or
--CH.sub.2C.sub.6H.sub.5, the --CH.sub.2C.sub.6H.sub.5 being
unsubstituted or substituted on the phenyl with one or more
methoxyl, halogen, methyl, nitro, trifluoromethyl, or
methoxylcarbonyl groups;
[0773] R.sub.3 is --CH.sub.3, --CH.sub.2CH.sub.3, or
--C.sub.6H.sub.5;
[0774] R.sub.7 is --H, a C.sub.1-C.sub.10 straight chain alkyl, or
--CH(CH.sub.3).sub.2; and
[0775] n is 4 to 8.
[0776] For use in the methods for inhibiting the replication or
infectivity of a virus, a preferred subclass of the compounds of
Formula (V) are those wherein:
[0777] R.sub.1 is --H;
[0778] R.sub.2 is --CH.sub.3, or --CH.sub.2C.sub.6H.sub.5;
[0779] R.sub.3 is --CH.sub.3;
[0780] R.sub.7 is --H or a C.sub.1-C.sub.4 straight or branched
chain alkyl; and
[0781] n is 4.
[0782] For use in the methods for inhibiting the replication or
infectivity of a virus, a more preferred subclass of the compounds
of Formula (V) are those wherein:
[0783] R.sub.1 is --H;
[0784] R.sub.2 and R.sub.3 is --CH.sub.3;
[0785] R.sub.7 is --H, --C.sub.2H.sub.5, or -n-C.sub.4H.sub.9;
and
[0786] n is 4.
[0787] The invention further provides methods for causing
immunosuppression in a patient comprising administering to a
patient in need thereof an effective amount of a compound of
Formula (V) or a pharmaceutically acceptable salt thereof, wherein,
in the compound of Formula (V):
[0788] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, and --C(O)OCH.sub.2C.sub.6H.sub.5;
[0789] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl, or
--CH.sub.2C.sub.6H.sub.5 the --CH.sub.2C.sub.6H.sub.5 being
unsubstituted or substituted on the phenyl with one or more
methoxyl, halogen, methyl, nitro, trifluoromethyl, or
methoxylcarbonyl groups;
[0790] R.sub.3 is --CH.sub.3, --CH.sub.2CH.sub.3, or
--C.sub.6H.sub.5;
[0791] R.sub.7 is --H, a C.sub.1-C.sub.10 straight chain alkyl, or
--CH(CH.sub.3).sub.2; and
[0792] n is 4 to 8.
[0793] For use in the methods for causing immunosuppression, a
preferred subclass of the compounds of Formula (V) are those
wherein:
[0794] R.sub.1 is --H;
[0795] R.sub.2 is --CH.sub.3, or --CH.sub.2C.sub.6H.sub.5;
[0796] R.sub.3 is --CH.sub.3;
[0797] R.sub.7 is --H or a C.sub.1-C.sub.4 straight or branched
chain alkyl; and
[0798] n is 4.
[0799] For use in the methods for causing immunosuppression, a more
preferred subclass of the compounds of Formula (V) are those
wherein:
[0800] R.sub.1 is --H;
[0801] R.sub.2 and R.sub.3 is --CH.sub.3.
[0802] R.sub.7 is --H, --C.sub.2H.sub.5, or -n-C.sub.4H.sub.9;
and
[0803] n is 4.
[0804] The invention further provides methods for treating or
preventing an autoimmune disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (V) or a
pharmaceutically acceptable salt thereof, wherein, in the compound
of Formula (V):
[0805] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, and --C(O)OCH.sub.2C.sub.6H.sub.5;
[0806] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl, or
--CH.sub.2C.sub.6H.sub.5, the --CH.sub.2C.sub.6H.sub.5 being
unsubstituted or substituted on the phenyl with one or more
methoxyl, halogen, methyl, nitro, trifluoromethyl, or
methoxylcarbonyl groups;
[0807] R.sub.3 is --CH.sub.3, --CH.sub.2CH.sub.3, or
--C.sub.6H.sub.5;
[0808] R.sub.7 is --H, a C.sub.1-C.sub.10 straight chain alkyl, or
--CH(CH.sub.3).sub.2; and
[0809] n is 4 to 8.
[0810] For use in the methods for treating or preventing an
autoimmune disease, a preferred subclass of the compounds of
Formula (V) are those wherein:
[0811] R.sub.1 is --H;
[0812] R.sub.2 is --CH.sub.3, or --CH.sub.2C.sub.6H.sub.5;
[0813] R.sub.3 is --CH.sub.3;
[0814] R.sub.7 is --H or a C.sub.1-C.sub.4 straight or branched
chain alkyl; and
[0815] n is 4.
[0816] For use in the methods for treating or preventing an
autoimmune disease, a more preferred subclass of the compounds of
Formula (V) are those wherein:
[0817] R.sub.1 is --H;
[0818] R.sub.2 and R.sub.3 is --CH.sub.3;
[0819] R.sub.7 is --H, --C.sub.2H.sub.5, or -n-C.sub.4H.sub.9;
and
[0820] n is 4.
5.6. Formula VI
[0821] The present invention encompasses novel compounds having the
general Formula (VI) and pharmaceutically acceptable salts thereof,
wherein:
[0822] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5;
[0823] R.sub.3 is a C.sub.1-C.sub.10 straight chain alkyl,
--CH(CH.sub.3).sub.2, --CH(CH.sub.3)CH.sub.2CH.sub.3,
--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.3,
--CH(OH)CH.sub.2CH.sub.2CH.sub.3, --CH(Cl)CH.sub.2CH.sub.2CH.sub.3,
or --CH.sub.2C.sub.6H.sub.5; and
[0824] n is 1 to 5.
[0825] The compounds of Formula (VI) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. The compounds of Formula (VI) or a pharmaceutically
acceptable salt thereof are also useful for inhibiting the growth
of a cancer cell or neoplastic cell. The compounds of Formula (VI)
or a pharmaceutically acceptable salt thereof are useful for
treating or preventing a viral infection in a patient in need of
such treatment or prevention. The compounds of Formula (VI) or a
pharmaceutically acceptable salt thereof are also useful for
inhibiting the replication or infectivity of a virus. The compounds
of Formula (VI) or a pharmaceutically acceptable salt thereof are
also useful for causing immunosuppression in a patient in need
thereof. The compounds of Formula (VI) or a pharmaceutically
acceptable salt thereof are also useful for treating an auto immune
disease in a patient in need of such treatment or prevention.
[0826] A preferred subclass of the compounds of Formula (VI) is
that wherein:
[0827] R.sub.2 is --CH.sub.3, or --CH.sub.2C.sub.6H.sub.5;
[0828] R.sub.3 is --H or C.sub.1-C.sub.4 straight or branched chain
alkyl; and
[0829] n is 1.
[0830] A more preferred subclass of the compounds of Formula (VI)
is that wherein:
[0831] R.sub.2 is --CH.sub.3;
[0832] R.sub.3 is -n-C.sub.4H.sub.9; and
[0833] n is 1.
[0834] The present invention also provides compositions comprising
a pharmaceutically acceptable carrier and an effective amount of a
compound of Formula (VI) or a pharmaceutically acceptable salt
thereof, wherein, in the compound of Formula (VI):
[0835] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5;
[0836] R.sub.3 is a C.sub.1-C.sub.10 straight chain alkyl,
--CH(CH.sub.3).sub.2, --CH(CH.sub.3)CH.sub.2CH.sub.3,
--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.3,
--CH(OH)CH.sub.2CH.sub.2CH.sub.3, --CH(Cl)CH.sub.2CH.sub.2CH.sub.3,
or --CH.sub.2C.sub.6H.sub.5; and
[0837] n is 1 to 5.
[0838] The compositions comprising a pharmaceutically acceptable
carrier and a compound of Formula (VI) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. These compositions are also useful for inhibiting
the growth of a cancer cell or neoplastic cell. The compositions
comprising a pharmaceutically acceptable carrier and a compound of
Formula (VI) or a pharmaceutically acceptable salt thereof are
useful for treating or preventing a viral infection in a patient in
need of such treatment or prevention. These compositions are also
useful for inhibiting the replication or infectivity of a virus.
The compositions comprising a pharmaceutically acceptable carrier
and a compound of Formula (VI) or a pharmaceutically acceptable
salt thereof are also useful for causing immunosuppression in a
patient in need thereof. The compositions comprising a
pharmaceutically acceptable carrier and a compound of Formula (VI)
or a pharmaceutically acceptable salt thereof are also useful for
treating an autoimmune disease in a patient in need of such
treatment or prevention.
[0839] A preferred subclass of the compositions comprising a
pharmaceutically acceptable carrier and a compound of Formula (VI)
or a pharmaceutically acceptable salt thereof is that wherein, in
the compound of Formula (VI):
[0840] R.sub.2 is --CH.sub.3, or --CH.sub.2C.sub.6H.sub.5;
[0841] R.sub.3 is --H or C.sub.1-C.sub.4 straight or branched chain
alkyl; and
[0842] n is 1.
[0843] A more preferred subclass of the compositions comprising a
pharmaceutically acceptable carrier and a compound of Formula (VI)
or a pharmaceutically acceptable salt thereof is that wherein, in
the compound of Formula (VI):
[0844] R.sub.2 is --CH.sub.3;
[0845] R.sub.3 is -n-C.sub.4H.sub.9; and
[0846] n is 1.
[0847] The invention further provides methods for treating or
preventing cancer or neoplastic disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective- amount of a compound of Formula (VI) or a
pharmaceutically acceptable salt thereof, wherein, in the compound
of Formula (VI):
[0848] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5;
[0849] R.sub.3 is a C.sub.1-C.sub.10 straight chain alkyl,
--CH(CH.sub.3).sub.2, --CH(CH.sub.3)CH.sub.2CH.sub.3,
--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.3,
--CH(OH)CH.sub.2CH.sub.2CH.sub.3, --CH(Cl)CH.sub.2CH.sub.2CH.sub.3,
or --CH.sub.2C.sub.6H.sub.5; and
[0850] n is 1 to 5.
[0851] For use in the methods for treating or preventing cancer or
neoplastic disease, a preferred subclass of the compounds of
Formula (VI) is that wherein, in the compound of Formula (VI):
[0852] R.sub.2 is --CH.sub.3, or --CH.sub.2C.sub.6H.sub.5;
[0853] R.sub.3 is --H or C.sub.1-C.sub.4 straight or branched chain
alkyl; and
[0854] n is 1.
[0855] For use in the methods for treating or preventing cancer or
neoplastic disease, a more preferred subclass of the compounds of
Formula (VI) is that wherein, in the compound of Formula (VI):
[0856] R.sub.2 is --CH.sub.3;
[0857] R.sub.3 is -n-C.sub.4H.sub.9; and
[0858] n is 1.
[0859] The invention further provides methods for inhibiting the
growth of a cancer cell or neoplastic cell comprising contacting a
cancer cell or neoplastic cell with an effective amount of a
compound having the general Formula (VI) or a pharmaceutically
acceptable salt thereof, wherein, in the compound of Formula
(VI):
[0860] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5;
[0861] R.sub.3 is a C.sub.1-C.sub.10 straight chain alkyl,
--CH(CH.sub.3).sub.2, --CH(CH.sub.3)CH.sub.2CH.sub.3,
--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.3,
--CH(OH)CH.sub.2CH.sub.2CH.sub.3, --CH(Cl)CH.sub.2CH.sub.2CH.sub.3,
or --CH.sub.2C.sub.6H.sub.5; and
[0862] n is 1 to 5.
[0863] For use in the methods for inhibiting the growth of a cancer
or neoplastic cell, a preferred subclass of the compounds of
Formula (VI) is that wherein, in the compound of Formula (VI):
[0864] R.sub.2 is --CH.sub.3, or --CH.sub.2C.sub.6H.sub.5;
[0865] R.sub.3 is --H or C.sub.1-C.sub.4 straight or branched chain
alkyl; and
[0866] n is 1.
[0867] For use in the methods for inhibiting the growth of a cancer
or neoplastic cell, a more preferred subclass of the compounds of
Formula (VI) is that wherein, in the compound of Formula (VI):
[0868] R.sub.2 is --CH.sub.3;
[0869] R.sub.3 is -n-C.sub.4H.sub.9; and
[0870] n is 1.
[0871] The invention further provides methods for treating or
preventing a viral infection in a patient comprising administering
to a patient in need of such treatment or prevention an effective
amount of a compound of Formula (VI) or a pharmaceutically
acceptable salt thereof, wherein, in the compound of Formula
(VI):
[0872] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5;
[0873] R.sub.3 is a C.sub.1-C.sub.10 straight chain alkyl,
--CH(CH.sub.3).sub.2, --CH(CH.sub.3)CH.sub.2CH.sub.3,
--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.3,
--CH(OH)CH.sub.2CH.sub.2CH.sub.3, --CH(Cl)CH.sub.2CH.sub.2CH.sub.3,
or --CH.sub.2C.sub.6H.sub.5; and
[0874] n is 1 to 5.
[0875] For use in the present methods for treating or preventing a
viral infection, a preferred subclass of the compounds of Formula
(VI) is that wherein, in the compound of Formula (VI):
[0876] R.sub.2 is --CH.sub.3, or --CH.sub.2C.sub.6H.sub.5;
[0877] R.sub.3 is --H or C.sub.1-C.sub.4 straight or branched chain
alkyl; and
[0878] n is 1.
[0879] For use in the present methods for treating or preventing a
viral infection, a more preferred subclass of the compounds of
Formula (VI) is that wherein, in the compound of Formula (VI):
[0880] R.sub.2 is --CH.sub.3;
[0881] R.sub.3 is -n-C.sub.4H.sub.9; and
[0882] n is 1.
[0883] The invention further provides methods for inhibiting the
replication or infectivity of a virus comprising contacting a virus
or a virus-infected cell with an effective amount of a compound
having the general Formula (VI) or a pharmaceutically acceptable
salt thereof, wherein, in the compound of Formula (VI):
[0884] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5;
[0885] R.sub.3 is a C.sub.1-C.sub.10 straight chain alkyl,
--CH(CH.sub.3).sub.2, --CH(CH.sub.3)CH.sub.2CH.sub.3,
--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.3,
--CH(OH)CH.sub.2CH.sub.2CH.sub.3, --CH(Cl)CH.sub.2CH.sub.2CH.sub.3,
or --CH.sub.2C.sub.6H.sub.5; and
[0886] n is 1 to 5.
[0887] For use in the methods for inhibiting the replication or
infectivity of a virus, a preferred subclass of the compounds of
Formula (VI) are those wherein:
[0888] R.sub.2 is --CH.sub.3, or --CH.sub.2C.sub.6H.sub.5;
[0889] R.sub.3 is --H or C.sub.1-C.sub.4 straight or branched chain
alkyl; and
[0890] n is 1.
[0891] For use in the methods for inhibiting the replication or
infectivity of a virus, a more preferred subclass of the compounds
of Formula (VI) are those wherein:
[0892] R.sub.2 is --CH.sub.3;
[0893] R.sub.3 is -n-C.sub.4H.sub.9; and
[0894] n is 1.
[0895] The invention further provides methods for causing
immunosuppression in a patient comprising administering to a
patient in need thereof an effective amount of a compound of
Formula (VI) or a pharmaceutically acceptable salt thereof,
wherein, in the compound of Formula (VI):
[0896] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5;
[0897] R.sub.3 is a C.sub.1-C.sub.10 straight chain alkyl,
--CH(CH.sub.3).sub.2, --CH(CH.sub.3)CH.sub.2CH.sub.3,
--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.3,
--CH(OH)CH.sub.2CH.sub.2CH.sub.3, --CH(CI)CH.sub.2CH.sub.2CH.sub.3,
or --CH.sub.2C.sub.6H.sub.5; and
[0898] n is 1 to 5.
[0899] For use in the methods for causing immunosuppression, a
preferred subclass of the compounds of Formula (VI) are those
wherein:
[0900] R.sub.2 is --CH.sub.3, or --CH.sub.2C.sub.6H.sub.5;
[0901] R.sub.3 is --H or C.sub.1-C.sub.4 straight or branched chain
alkyl; and
[0902] n is 1.
[0903] For use in the methods for causing immunosuppression, a more
preferred subclass of the compounds of Formula (VI) are those
wherein:
[0904] R.sub.2 is --CH.sub.3;
[0905] R.sub.3 is -n-C.sub.4H.sub.9; and
[0906] n is 1.
[0907] The invention further provides methods for treating or
preventing an autoimmune disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (VI) or a
pharmaceutically acceptable salt thereof, wherein, in the compound
of Formula (VI):
[0908] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5;
[0909] R.sub.3 is a C.sub.1-C.sub.10 straight chain alkyl,
--CH(CH.sub.3).sub.2, --CH(CH.sub.3)CH.sub.2CH.sub.3,
--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.3,
--CH(OH)CH.sub.2CH.sub.2CH.sub.3, --CH(Cl)CH.sub.2CH.sub.2CH.sub.3,
or --CH.sub.2C.sub.6H.sub.5; and
[0910] n is 1 to 5.
[0911] For use in the methods for treating or preventing an
autoimmune disease, a preferred subclass of the compounds of
Formula (VI) are those wherein:
[0912] R.sub.2 is --CH.sub.3, or --CH.sub.2C.sub.6H.sub.5;
[0913] R.sub.3 is --H or C.sub.1-C.sub.4 straight or branched chain
alkyl; and
[0914] n is 1.
[0915] For use in the methods for treating or preventing an
autoimmune disease, a more preferred subclass of the compounds of
Formula (VI) are those wherein:
[0916] R.sub.2 is --CH.sub.3;
[0917] R.sub.3 is -n-C.sub.4H.sub.9; and
[0918] n is 1.
5.7. Formula VII
[0919] The present invention encompasses novel compounds having the
general Formula (VII) and pharmaceutically acceptable salts
thereof, wherein:
[0920] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5; and
[0921] R.sub.4 is --H or a C.sub.1-C.sub.15 straight chain
alkyl.
[0922] The compounds of Formula (VII) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. The compounds of Formula (VII) or a pharmaceutically
acceptable salt thereof are also useful for inhibiting the growth
of a cancer cell or neoplastic cell. The compounds of Formula (VII)
or a pharmaceutically acceptable salt thereof are useful for
treating or preventing a viral infection in a patient in need of
such treatment or prevention. The compounds of Formula (VII) or a
pharmaceutically acceptable salt thereof are also useful for
inhibiting the replication or infectivity of a virus. The compounds
of Formula (VII) or a pharmaceutically acceptable salt thereof are
also useful for causing immunosuppression in a patient in need
thereof. The compounds of Formula (VII) or a pharmaceutically
acceptable salt thereof are also useful for treating an autoimmune
disease in a patient in need of such treatment or prevention.
[0923] A preferred subclass of the compounds of Formula (VII) is
that wherein:
[0924] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5; and
[0925] R.sub.4 is --H, --CH.sub.3, or
(CH.sub.2).sub.14CH.sub.3.
[0926] A more preferred subclass of the compounds of Formula (VII)
is that wherein:
[0927] R.sub.2 is --CH.sub.3; and
[0928] R.sub.4 is --H, --CH.sub.3, or
(CH.sub.2).sub.14CH.sub.3.
[0929] The present invention also provides compositions comprising
a pharmaceutically acceptable carrier and an effective amount of a
compound of Formula (VII) or a pharmaceutically acceptable salt
thereof, wherein, in the compound of Formula (VII):
[0930] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5; and
[0931] R.sub.4 is --H or a C.sub.1-C.sub.15 straight chain
alkyl.
[0932] The compositions comprising a pharmaceutically acceptable
carrier and a compound of Formula (VII) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. These compositions are also useful for inhibiting
the growth of a cancer cell or neoplastic cell. The compositions
comprising a pharmaceutically acceptable carrier and a compound of
Formula (VII) or a pharmaceutically acceptable salt thereof are
useful for treating or preventing a viral infection in a patient in
need of such treatment or prevention. These compositions are also
useful for inhibiting the replication or infectivity of a virus.
The compositions comprising a pharmaceutically acceptable carrier
and a compound of Formula (VII) or a pharmaceutically acceptable
salt thereof are also useful for causing immunosuppression in a
patient in need thereof. The compositions comprising a
pharmaceutically acceptable carrier and a compound of Formula (VII)
or a pharmaceutically acceptable salt thereof are also useful for
treating an autoimmune disease in a patient in need of such
treatment or prevention.
[0933] A preferred subclass of the compositions comprising a
pharmaceutically acceptable carrier and a compound of Formula (VII)
or a pharmaceutically acceptable salt thereof is that wherein, in
the compound of Formula (VII):
[0934] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5; and
[0935] R.sub.4 is --H, --CH.sub.3, or
(CH.sub.2).sub.14CH.sub.3.
[0936] A more preferred subclass of the compositions comprising a
pharmaceutically acceptable carrier and a compound of Formula (VII)
or a pharmaceutically acceptable salt thereof is that wherein, in
the compound of Formula (VII):
[0937] R.sub.2 is --CH.sub.3; and
[0938] R.sub.4 is --H, --CH.sub.3, or
(CH.sub.2).sub.14CH.sub.3.
[0939] The invention further provides methods for treating or
preventing cancer or neoplastic disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective arnount of a compound of Formula (VII) or a
pharmaceutically acceptable salt thereof, wherein, in the compound
of Formula (VII):
[0940] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5; and
[0941] R.sub.4 is --H or a C.sub.1-C.sub.15 straight chain
alkyl.
[0942] For use in the methods for treating or preventing cancer or
neoplastic disease, a preferred subclass of the compounds of
Formula (VII) is that wherein, in the compound of Formula
(VII):
[0943] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5; and
[0944] R.sub.4 is --H, --CH.sub.3, or
(CH.sub.2).sub.14CH.sub.3.
[0945] For use in the methods for treating or preventing cancer or
neoplastic disease, a more preferred subclass of the compounds of
Formula (VII) is that wherein, in the compound of Formula
(VII):
[0946] R.sub.2 is --CH.sub.3; and
[0947] R.sub.4 is --H, --CH.sub.3, or
(CH.sub.2).sub.14CH.sub.3.
[0948] The invention further provides methods for inhibiting the
growth of a cancer cell or neoplastic cell comprising contacting a
cancer cell or neoplastic cell with an effective amount of a
compound having the general Formula (VII) or a pharmaceutically
acceptable salt thereof, wherein, in the compound of Formula
(VII):
[0949] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5; and
[0950] R.sub.4 is --H or a C.sub.1-C.sub.15 straight chain
alkyl.
[0951] For use in the methods for inhibiting the growth of a cancer
or neoplastic cell, a preferred subclass of the compounds of
Formula (VII) is that wherein, in the compound of Formula
(VII):
[0952] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5; and
[0953] R.sub.4 is --H, --CH.sub.3, or
(CH.sub.2).sub.14CH.sub.3.
[0954] For use in the methods for inhibiting the growth of a cancer
or neoplastic cell, a more preferred subclass of the compounds of
Formula (VII) is that wherein, in the compound of Formula
(VII):
[0955] R.sub.2 is --CH.sub.3; and
[0956] R.sub.4 is --H, --CH.sub.3, or
(CH.sub.2).sub.14CH.sub.3.
[0957] The invention further provides methods for treating or
preventing a viral infection in a patient comprising administering
to a patient in need of such treatment or prevention an effective
amount of a compound of Formula (VII) or a pharmaceutically
acceptable salt thereof, wherein, in the compound of Formula
(VII):
[0958] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5; and
[0959] R.sub.4 is --H or a C.sub.1-C.sub.15 straight chain
alkyl.
[0960] For use in the present methods for treating or preventing a
viral infection, a preferred subclass of the compounds of Formula
(VII) is that wherein, in the compound of Formula (VII):
[0961] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5; and
[0962] R.sub.4 is --H, --CH.sub.3 or (CH.sub.2).sub.14CH.sub.3.
[0963] For use in the present methods for treating or preventing a
viral infection, a more preferred subclass of the compounds of
Formula (VII) is that wherein, in the compound of Formula
(VII):
[0964] R.sub.2 is --CH.sub.3; and
[0965] R.sub.4 is --H, --CH.sub.3, or
(CH.sub.2).sub.14CH.sub.3.
[0966] The invention further provides methods for inhibiting the
replication or infectivity of a virus comprising contacting a virus
or a virus-infected cell with an effective amount of a compound
having the general Formula (VII) or a pharmaceutically acceptable
salt thereof, wherein, in the compound of Formula (VII):
[0967] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5; and
[0968] R.sub.4 is --H or a C.sub.1-C.sub.15 straight chain
alkyl.
[0969] For use in the methods for inhibiting the replication or
infectivity of a virus, a preferred subclass of the compounds of
Formula (VII) are those wherein:
[0970] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5; and
[0971] R.sub.4 is --H, --CH.sub.3, or
(CH.sub.2).sub.14CH.sub.3.
[0972] For use in the methods for inhibiting the replication or
infectivity of a virus, a more preferred subclass of the compounds
of Formula (VII) are those wherein:
[0973] R.sub.2 is --CH.sub.3; and
[0974] R.sub.4 is --H, --CH.sub.3, or
(CH.sub.2).sub.14CH.sub.3.
[0975] The invention further provides methods for causing
immunosuppression in a patient comprising administering to a
patient in need thereof an effective amount of a compound of
Formula (VII) or a pharmaceutically acceptable salt thereof,
wherein, in the compound of Formula (VII):
[0976] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5; and
[0977] R.sub.4 is --H or a C.sub.1-C.sub.15 straight chain
alkyl.
[0978] For use in the methods for causing immunosuppression, a
preferred subclass of the compounds of Formula (VII) are those
wherein:
[0979] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5; and
[0980] R.sub.4 is --H, --CH.sub.3, or
(CH.sub.2).sub.14CH.sub.3.
[0981] For use in the methods for causing immunosuppression, a more
preferred subclass of the compounds of Formula (VII) are those
wherein:
[0982] R.sub.2 is --CH.sub.3; and
[0983] R.sub.4 is --H, --CH.sub.3, or
(CH.sub.2).sub.14CH.sub.3.
[0984] The invention further provides methods for treating or
preventing an autoimmune disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (VII) or a
pharmaceutically acceptable salt thereof, wherein, in the compound
of Formula (VII):
[0985] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5; and
[0986] R.sub.4 is --H or a C.sub.1-C.sub.15 straight chain
alkyl.
[0987] For use in the methods treating or preventing an autoimmune
disease, a preferred subclass of the compounds of Formula (VII) are
those wherein:
[0988] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5; and
[0989] R.sub.4 is --H, --CH.sub.3, or
(CH.sub.2).sub.14CH.sub.3.
[0990] For use in the methods for treating or preventing an
autoimmune disease, a more preferred subclass of the compounds of
Formula (VII) are those wherein:
[0991] R.sub.2 is --CH.sub.3; and
[0992] R.sub.4 is --H, --CH.sub.3, or
(CH.sub.2).sub.14CH.sub.3.
5.8. Formula VIII
[0993] The present invention encompasses novel compounds having the
general Formula (VIII) and pharmaceutically acceptable salts
thereof, wherein:
[0994] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5;
[0995] R.sub.4 is --H or a C.sub.1-C.sub.10 straight chain
alkyl;
[0996] R.sub.5 is --H or a C.sub.1-C.sub.10 straight chain alkyl;
and
[0997] m is 1 to 4.
[0998] The compounds of Formula (VIII) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. The compounds of Formula (VIII) or a
pharmaceutically acceptable salt thereof are also useful for
inhibiting the growth of a cancer cell or neoplastic cell. The
compounds of Formula (VIII) or a pharmaceutically acceptable salt
thereof are useful for treating or preventing a viral infection in
a patient in need of such treatment or prevention. The compounds of
Formula (VII) or a pharmaceutically acceptable salt thereof are
also useful for inhibiting the replication or infectivity of a
virus. The compounds of Formula (VIII) or a pharmaceutically
acceptable salt thereof are also useful for causing
immunosuppression in a patient in need thereof. The compounds of
Formula (VIII) or a pharmaceutically acceptable salt thereof are
also useful for treating an autoimmune disease in a patient in need
of such treatment or prevention.
[0999] A preferred subclass of the compounds of Formula (VIII) is
that wherein:
[1000] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5;
[1001] R.sub.4 and R.sub.5 is --H or --CH.sub.3; and
[1002] m is 2.
[1003] A more preferred subclass of the compounds of Formula (VIII)
is that wherein:
[1004] R.sub.2 and R.sub.5 is --CH.sub.3;
[1005] R.sub.4 is --H or --CH.sub.3; and
[1006] m is 2.
[1007] The present invention also provides compositions comprising
a pharmaceutically acceptable carrier and an effective amount of a
compound of Formula (VIII) or a pharmaceutically acceptable salt
thereof, wherein, in the compound of Formula (VIII):
[1008] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5;
[1009] R.sub.5 is --H or a C.sub.1-C.sub.10 straight chain
alkyl;
[1010] R.sub.4 is --H or a C.sub.1-C.sub.10 straight chain alkyl;
and
[1011] m is 1 to 4.
[1012] The compositions comprising a pharmaceutically acceptable
carrier and a compound of Formula (VIII) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. These compositions are also useful for inhibiting
the growth of a cancer cell or neoplastic cell. The compositions
comprising a pharmaceutically acceptable carrier and a compound of
Formula (VIII) or a pharmaceutically acceptable salt thereof are
useful for treating or preventing a viral infection in a patient in
need of such treatment or prevention. These compositions are also
useful for inhibiting the replication or infectivity of a virus.
The compositions comprising a pharmaceutically acceptable carrier
and a compound of Formula (VIII) or a pharmaceutically acceptable
salt thereof are also useful for causing immunosuppression in a
patient in need thereof. The compositions comprising a
pharmaceutically acceptable carrier and a compound of Formula
(VIII) or a pharmaceutically acceptable salt thereof are also
useful for treating an autoimmune disease in a patient in need of
such treatment or prevention.
[1013] A preferred subclass of the compositions comprising a
pharmaceutically acceptable carrier and a compound of Formula
(VIII) or a pharmaceutically acceptable salt thereof is that
wherein, in the compound of Formula (VIII):
[1014] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5;
[1015] R.sub.4 and R.sub.5 is --H or --CH.sub.3; and
[1016] m is 2.
[1017] A more preferred subclass of the compositions comprising a
pharmaceutically acceptable carrier and a compound of Formula
(VIII) or a pharmaceutically acceptable salt thereof is that
wherein, in the compound of Formula (VIII):
[1018] R.sub.2 and R.sub.5 is --CH.sub.3;
[1019] R.sub.4 is --H or --CH.sub.3; and
[1020] m is 2.
[1021] The invention further provides methods for treating or
preventing cancer or neoplastic disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (VIII) or a
pharmaceutically acceptable salt thereof, wherein, in the compound
of Formula (VIII):
[1022] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5;
[1023] R.sub.4 is --H or a C.sub.1-C.sub.10 straight chain
alkyl;
[1024] R.sub.5 is --H or a C.sub.1-C.sub.10 straight chain alkyl;
and
[1025] m is 1 to 4.
[1026] For use in the methods for treating or preventing cancer or
neoplastic disease, a preferred subclass of the compounds of
Formula (VIII) is that wherein, in the compound of Formula
(VIII):
[1027] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5;
[1028] R.sub.4 and R.sub.5 is --H or --CH.sub.3; and
[1029] m is 2.
[1030] For use in the methods for treating or preventing cancer or
neoplastic disease, a more preferred subclass of the compounds of
Formula (VIII) is that wherein, in the compound of Formula
(VIII):
[1031] R.sub.2 and R.sub.5 is --CH.sub.3;
[1032] R.sub.4 is --H or --CH.sub.3; and
[1033] m is 2.
[1034] The invention further provides methods for inhibiting the
growth of a cancer cell or neoplastic cell comprising contacting a
cancer cell or neoplastic cell with an effective amount of a
compound having the general Formula (VIII) or a pharmaceutically
acceptable salt thereof, wherein, in the compound of Formula
(VIII):
[1035] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5;
[1036] R.sub.4 is --H or a C.sub.1-C.sub.10 straight chain
alkyl;
[1037] R.sub.5 is --H or a C.sub.1-C.sub.10 straight chain alkyl;
and
[1038] m is 1 to 4.
[1039] For use in the methods for inhibiting the growth of a cancer
or neoplastic cell, a preferred subclass of the compounds of
Formula (VIII) is that wherein, in the compound of Formula
(VIII):
[1040] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5;
[1041] R.sub.4 and R.sub.5 is --H or --CH.sub.3; and
[1042] m is 2.
[1043] For use in the methods for inhibiting the growth of a cancer
or neoplastic cell, a more preferred subclass of the compounds of
Formula (VIII) is that wherein, in the compound of Formula
(VIII):
[1044] R.sub.2 and R.sub.5 is --CH.sub.3;
[1045] R.sub.4 is --H or --CH.sub.3; and
[1046] m is 2.
[1047] The invention further provides methods for treating or
preventing a viral infection in a patient comprising administering
to a patient in need of such treatment or prevention an effective
amount of a compound of Formula (VIII) or a pharmaceutically
acceptable salt thereof, wherein, in the compound of Formula
(VIII):
[1048] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5;
[1049] R.sub.5 is --H or a C.sub.1-C.sub.10 straight chain
alkyl;
[1050] R.sub.4 is --H or a C.sub.1-C.sub.10 straight chain alkyl;
and
[1051] m is 1 to 4.
[1052] For use in the present methods for treating or preventing a
viral infection, a preferred subclass of the compounds of Formula
(VIII) is that wherein, in the compound of Formula (VIII):
[1053] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5;
[1054] R.sub.4 and R.sub.5 is --H or --CH.sub.3; and
[1055] m is 2.
[1056] For use in the present methods for treating or preventing a
viral infection, a more preferred subclass of the compounds of
Formula (VIII) is that wherein, in the compound of Formula
(VIII):
[1057] R.sub.2 and R.sub.5 is --CH.sub.3;
[1058] R.sub.4 is --H or --CH.sub.3; and
[1059] m is 2.
[1060] The invention further provides methods for inhibiting the
replication or infectivity of a virus comprising contacting a virus
or a virus-infected cell with an effective amount of a compound
having the general Formula (VIII) or a pharmaceutically acceptable
salt thereof, wherein, in the compound of Formula (VIII):
[1061] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5;
[1062] R.sub.4 is --H or a C.sub.1-C.sub.10 straight chain
alkyl;
[1063] R.sub.5 is --H or a C.sub.1-C.sub.10 straight chain alkyl;
and
[1064] m is 1 to 4.
[1065] For use in the methods for inhibiting the replication or
infectivity of a virus, a preferred subclass of the compounds of
Formula (VIII) are those wherein:
[1066] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5;
[1067] R.sub.4 and R.sub.5 is --H or --CH.sub.3; and
[1068] m is 2.
[1069] For use in the methods for inhibiting the replication or
infectivity of a virus, a more preferred subclass of the compounds
of Formula (VIII) are those wherein:
[1070] R.sub.2 and R.sub.5 is --CH.sub.3;
[1071] R.sub.4 is --H or --CH.sub.3; and
[1072] m is 2.
[1073] The invention further provides methods for causing
immunosuppression in a patient comprising administering to a
patient in need thereof an effective amount of a compound of
Formula (VIII) or a pharmaceutically acceptable salt thereof,
wherein, in the compound of Formula (VIII):
[1074] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5;
[1075] R.sub.4 is --H or a C.sub.1-C.sub.10 straight chain
alkyl;
[1076] R.sub.5 is --H or a C.sub.1-C.sub.10 straight chain alkyl;
and
[1077] m is 1 to 4.
[1078] For use in the methods for causing immunosuppression, a
preferred subclass of the compounds of Formula (VIII) are those
wherein:
[1079] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5;
[1080] R.sub.4 and R.sub.5 is --H or --CH.sub.3; and
[1081] m is 2.
[1082] For use in the methods for causing immunosuppression, a more
preferred subclass of the compounds of Formula (VIII) are those
wherein:
[1083] R.sub.2 and R.sub.5 is --CH.sub.3;
[1084] R.sub.4 is --H or --CH.sub.3; and
[1085] m is 2.
[1086] The invention further provides methods for treating or
preventing an autoimmune disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (VIII) or a
pharmaceutically acceptable salt thereof, wherein, in the compound
of Formula (VIII):
[1087] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5;
[1088] R.sub.4 is --H or a C.sub.1-C.sub.10 straight chain
alkyl;
[1089] R.sub.5 is --H or a C.sub.1-C.sub.10 straight chain alkyl;
and
[1090] m is 1 to 4.
[1091] For use in the methods for treating or preventing an
autoimmune disease, a preferred subclass of the compounds of
Formula (VIII) are those wherein:
[1092] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5;
[1093] R.sub.4 and R.sub.5 is --H or --CH.sub.3; and
[1094] m is 2.
[1095] For use in the methods for treating or preventing an
autoimmune disease, a more preferred subclass of the compounds of
Formula (VIII) are those wherein:
[1096] R.sub.2 and R.sub.5 is --CH.sub.3;
[1097] R.sub.4 is --H or --CH.sub.3; and
[1098] m is 2.
5.9. Formula IX
[1099] The present invention encompasses novel compounds having the
general Formula (IX) and pharmaceutically acceptable salts thereof,
wherein:
[1100] R.sub.1 is --H, --CH.sub.3, --SO.sub.2-4-methylphenyl,
--CH.sub.2C.sub.6H.sub.5, --Si(R.sub.5R.sub.6R.sub.7),
--CH.sub.2OCH.sub.2CH.sub.2SiCH.sub.3, --C(O)OC(CH.sub.3).sub.3, or
--C(O)CH.sub.2C.sub.6H.sub.5;
[1101] R.sub.2 is --CH.sub.3, --CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub- .3, or --CH.sub.2C.sub.6H.sub.5;
[1102] R.sub.3 is --H or Cl;
[1103] R.sub.4 is --H or a C.sub.1-C.sub.10 straight chain
alkyl;
[1104] R.sub.5 is a C.sub.1-C.sub.4 straight or branched chain
alkyl or --C.sub.6H.sub.5;
[1105] R.sub.6 is a C.sub.1-C.sub.3 straight or branched chain
alkyl;
[1106] R.sub.7 is a C.sub.1-C.sub.3 straight or branched chain
alkyl; and
[1107] n is 1 to 5.
[1108] The compounds of Formula (IX) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. The compounds of Formula (IX) or a pharmaceutically
acceptable salt thereof are also useful for inhibiting the growth
of a cancer cell or neoplastic cell. The compounds of Formula (IX)
or a pharmaceutically acceptable salt thereof are useful for
treating or preventing a viral infection in a patient in need of
such treatment or prevention. The compounds of Formula (IX) or a
pharmaceutically acceptable salt thereof are also useful for
inhibiting the replication or infectivity of a virus. The compounds
of Formula (IX) or a pharmaceutically acceptable salt thereof are
also useful for causing immunosuppression in a patient in need
thereof. The compounds of Formula (IX) or a pharmaceutically
acceptable salt thereof are also useful for treating an autoimmune
disease in a patient in need of such treatment or prevention.
[1109] A preferred subclass of the compounds of Formula (IX) is
that wherein:
[1110] R.sub.1 is --H;
[1111] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5;
[1112] R.sub.3 is --H;
[1113] R.sub.4 is --H or a C.sub.1-C.sub.4 straight or branched
chain alkyl; and
[1114] n is 1 to 3.
[1115] A more preferred subclass of the compounds of Formula (IX)
is that wherein:
[1116] R.sub.1 is --H;
[1117] R.sub.2 is --CH.sub.3;
[1118] R.sub.3 is --H;
[1119] R.sub.4 is --C.sub.4H.sub.9; and
[1120] n is 1.
[1121] Another more preferred subclass of the compounds of Formula
(IX) is that wherein:
[1122] R.sub.1 is --H;
[1123] R.sub.2 is --CH.sub.3;
[1124] R.sub.3 is --H;
[1125] R.sub.4 is --C.sub.2H.sub.5; and
[1126] n is 3.
[1127] The present invention also provides compositions comprising
a pharmaceutically acceptable carrier and an effective amount of a
compound of Formula (IX) or a pharmaceutically acceptable salt
thereof, wherein, in the compound of Formula (IX):
[1128] R.sub.1 is --H, --CH.sub.3, --SO.sub.2-4-methylphenyl,
--CH.sub.2C.sub.6H.sub.5, --Si(R.sub.5R.sub.6R.sub.7),
--CH.sub.2OCH.sub.2CH.sub.2SiCH.sub.3, --C(O)OC(CH.sub.3).sub.3, or
--C(O)CH.sub.2C.sub.6H.sub.5;
[1129] R.sub.2 is --CH.sub.3, --CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub- .3, or --CH.sub.2C.sub.6H.sub.5;
[1130] R.sub.3 is --H or Cl;
[1131] R.sub.4 is --H or a C.sub.1-C.sub.10 straight chain
alky;
[1132] R.sub.5 is a C.sub.1-C.sub.4 straight or branched chain
alkyl or --C.sub.6H.sub.5;
[1133] R.sub.6 is a C.sub.1-C.sub.3 straight or branched chain
alkyl;
[1134] R.sub.7 is a C.sub.1-C.sub.3 straight or branched chain
alkyl; and
[1135] n is 1 to 5.
[1136] The compositions comprising a pharmaceutically acceptable
carrier and a compound of Formula (IX) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. These compositions are also useful for inhibiting
the growth of a cancer cell or neoplastic cell. The compositions
comprising a pharmaceutically acceptable carrier and a compound of
Formula (IX) or a pharmaceutically acceptable salt thereof are
useful for treating or preventing a viral infection in a patient in
need of such treatment or prevention. These compositions are also
useful for inhibiting the replication or infectivity of a virus.
The compositions comprising a pharmaceutically acceptable carrier
and a compound of Formula (IX) or a pharmaceutically acceptable
salt thereof are also useful for causing immunosuppression in a
patient in need thereof. The compositions comprising a
pharmaceutically acceptable carrier and a compound of Formula (IX)
or a pharmaceutically acceptable salt thereof are also useful for
treating an autoimmune disease in a patient in need of such
treatment or prevention.
[1137] A preferred subclass of the compositions comprising a
pharmaceutically acceptable carrier and a compound of Formula (IX)
or a pharmaceutically acceptable salt thereof is that wherein, in
the compound of Formula (IX):
[1138] R.sub.1 is --H;
[1139] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5;
[1140] R.sub.3 is --H;
[1141] R.sub.4 is --H or a C.sub.1-C.sub.4 straight or branched
chain alkyl; and
[1142] n is 1 to 3.
[1143] A more preferred subclass of the compositions comprising a
pharmaceutically acceptable carrier and a compound of Formula (IX)
or a pharmaceutically acceptable salt thereof is that wherein, in
the compound of Formula (I):
[1144] R.sub.1 is --H;
[1145] R.sub.2 is --CH.sub.3;
[1146] R.sub.3 is --H;
[1147] R.sub.4 is --C.sub.4H.sub.9; and
[1148] n is 1.
[1149] Another more preferred subclass of the compositions
comprising a pharmaceutically acceptable carrier and a compound of
Formula (IX) or a pharmaceutically acceptable salt thereof is that
wherein, in the compound of Formula (IX):
[1150] R.sub.1 is --H;
[1151] R.sub.2 is --CH.sub.3;
[1152] R.sub.3 is --H;
[1153] R.sub.4 is --C.sub.2H.sub.5; and
[1154] n is 3.
[1155] The invention further provides methods for treating or
preventing cancer or neoplastic disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (IX) or a
pharmaceutically acceptable salt thereof, wherein, in the compound
of Formula (IX) R.sub.1 is --H, --CH.sub.3,
--SO.sub.2-4-methylphenyl, --CH.sub.2C.sub.6H.sub.5,
--Si(R.sub.5R.sub.6R.sub.7), --CH.sub.2OCH.sub.2CH.sub.2SiCH.sub.3,
--C(O)OC(CH.sub.3).sub.3, or --C(O)CH.sub.2C.sub.6H.sub.5;
[1156] R.sub.2 is --CH.sub.3, --CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub- .3, or --CH.sub.2C.sub.6H.sub.5;
[1157] R.sub.3 is --H or Cl;
[1158] R.sub.4 is --H or a C.sub.1-C.sub.10 straight chain
alkyl;
[1159] R.sub.5 is a C.sub.1-C.sub.4 straight or branched chain
alkyl or --C.sub.6H.sub.5;
[1160] R.sub.6 is a C.sub.1-C.sub.3 straight or branched chain
alkyl;
[1161] R.sub.7 is a C.sub.1-C.sub.3 straight or branched chain
alkyl; and
[1162] n is 1 to 5.
[1163] For use in the methods for treating or preventing cancer or
neoplastic disease, a preferred subclass of the compounds of
Formula (IX) is that wherein, in the compound of Formula (IX):
[1164] R.sub.1 is --H;
[1165] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5;
[1166] R.sub.3 is --H;
[1167] R.sub.4 is --H or a C.sub.1-C.sub.4 straight or branched
chain alkyl; and
[1168] n is 1 to 3.
[1169] For use in the methods for treating or preventing cancer or
neoplastic disease, a more preferred subclass of the compounds of
Formula (IX) is that wherein, in the compound of Formula (IX):
[1170] R.sub.1 is --H;
[1171] R.sub.2 is --CH.sub.3;
[1172] R.sub.3 is --H;
[1173] R.sub.4 is --C.sub.4H.sub.9; and
[1174] n is 1.
[1175] For use in the methods for treating or preventing cancer or
neoplastic disease, another more preferred subclass of the
compounds of Formula (IX) is that wherein, in the compound of
Formula (XI):
[1176] R.sub.1 is --H;
[1177] R.sub.2 is --CH.sub.3;
[1178] R.sub.3 is --H;
[1179] R.sub.4 is --C.sub.2H.sub.5; and
[1180] n is 3.
[1181] The invention further provides methods for inhibiting the
growth of a cancer cell or neoplastic cell comprising contacting a
cancer cell or neoplastic cell with an effective amount of a
compound having the general Formula (IX) or a pharmaceutically
acceptable salt thereof, wherein, in the compound of Formula
(IX):
[1182] R.sub.1 is --H, --CH.sub.3, --SO.sub.2-4-methylphenyl,
--CH.sub.2C.sub.6H.sub.5, --Si(R.sub.5R.sub.6R.sub.7),
--CH.sub.2OCH.sub.2CH.sub.2SiCH.sub.3, --C(O)OC(CH.sub.3).sub.3, or
--C(O)CH.sub.2C.sub.6H.sub.5;
[1183] R.sub.2 is --CH.sub.3, --CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub- .3, or --CH.sub.2C.sub.6H.sub.5;
[1184] R.sub.3 is --H or Cl;
[1185] R.sub.4 is --H or a C.sub.1-C.sub.10 straight chain
alkyl;
[1186] R.sub.5 is a C.sub.1-C.sub.4 straight or branched chain
alkyl or --C.sub.6H.sub.5;
[1187] R.sub.6 is a C.sub.1-C.sub.3 straight or branched chain
alkyl;
[1188] R.sub.7 is a C.sub.1-C.sub.3 straight or branched chain
alkyl; and
[1189] n is I to 5.
[1190] For use in the methods for inhibiting the growth of a cancer
or neoplastic cell, a preferred subclass of the compounds of
Formula (IX) is that wherein, in the compound of Formula (IX):
[1191] R.sub.1 is --H;
[1192] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5;
[1193] R.sub.3 is --H;
[1194] R.sub.4 is --H or a C.sub.1-C.sub.4 straight or branched
chain alkyl; and
[1195] n is 1 to 3.
[1196] For use in the methods for inhibiting the growth of a cancer
or neoplastic cell, a more preferred subclass of the compounds of
Formula (IX) is that wherein, in the compound of Formula (IX):
[1197] R.sub.1 is --H;
[1198] R.sub.2 is --CH.sub.3;
[1199] R.sub.3 is --H;
[1200] R.sub.4 is --C.sub.4H.sub.9; and
[1201] n is 1.
[1202] For use in the methods for inhibiting the growth of a cancer
or neoplastic cell, another more preferred subclass of the
compounds of Formula (IX) is that wherein, in the compound of
Formula (IX):
[1203] R.sub.1 is --H;
[1204] R.sub.2 is --CH.sub.3;
[1205] R.sub.3 is --H;
[1206] R.sub.4 is --C.sub.2H.sub.5; and
[1207] n is 3.
[1208] The invention further provides methods for treating or
preventing a viral infection in a patient comprising administering
to a patient in need of such treatment or prevention an effective
amount of a compound of Formula (IX) or a pharmaceutically
acceptable salt thereof, wherein, in the compound of Formula
(IX):
[1209] R.sub.1 is --H, --CH.sub.3, --SO.sub.2-4-methylphenyl,
--CH.sub.2C.sub.6H.sub.5, --Si(R.sub.5R.sub.6,R.sub.7),
--CH.sub.2OCH.sub.2CH.sub.2SiCH.sub.3, --C(O)OC(CH.sub.3).sub.3, or
--C(O)CH.sub.2C.sub.6H.sub.5;
[1210] R.sub.2 is --CH.sub.3, --CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub- .3, or --CH.sub.2C.sub.6H.sub.5;
[1211] R.sub.3 is --H or Cl;
[1212] R.sub.4 is --H or a C.sub.1-C.sub.10 straight chain
alkyl;
[1213] R.sub.5 is a C.sub.1-C.sub.4 straight or branched chain
alkyl or --C.sub.6H.sub.5;
[1214] R.sub.6 is a C.sub.1-C.sub.3 straight or branched chain
alkyl;
[1215] R.sub.7 is a C.sub.1-C.sub.3 straight or branched chain
alkyl; and
[1216] n is 1 to 5.
[1217] For use in the present methods for treating or preventing a
viral infection, a preferred subclass of the compounds of Formula
(IX) is that wherein, in the compound of Formula (IX):
[1218] R.sub.1 is --H;
[1219] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H;
[1220] R.sub.3 is --H;
[1221] R.sub.4 is --H or a C.sub.1-C.sub.4 straight or branched
chain alkyl; and
[1222] n is 1 to 3.
[1223] For use in the present methods for treating or preventing a
viral infection, a more preferred subclass of the compounds of
Formula (IX) is that wherein, in the compound of Formula (IX):
[1224] R.sub.1 is --H;
[1225] R.sub.2 is --CH.sub.3;
[1226] R.sub.3 is --H;
[1227] R.sub.4 is --C.sub.4H.sub.9; and
[1228] n is 1.
[1229] For use in the present methods for treating or preventing a
viral infection, another more preferred subclass of the compounds
of Formula (IX) is that wherein, in the compound of Formula
(IX):
[1230] R.sub.1 is --H;
[1231] R.sub.2 is --CH.sub.3;
[1232] R.sub.3 is --H;
[1233] R.sub.4 is --C.sub.2H.sub.5; and
[1234] n is 3.
[1235] The invention further provides methods for inhibiting the
replication or infectivity of a virus comprising contacting a virus
or a virus-infected cell with an effective amount of a compound
having the general Formula (IX) or a pharmaceutically acceptable
salt thereof, wherein, in the compound of Formula (IX):
[1236] R.sub.1 is --H, --CH.sub.3, --SO.sub.2-4-methylphenyl,
--CH.sub.2C.sub.6H.sub.5, --Si(R.sub.5R.sub.6R.sub.7),
--CH.sub.2OCH.sub.2CH.sub.2SiCH.sub.3, --C(O)OC(CH.sub.3).sub.3, or
--C(O)CH.sub.2C.sub.6H.sub.5;
[1237] R.sub.2 is --CH.sub.3, --CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub- .3, or --CH.sub.2C.sub.6H.sub.5;
[1238] R.sub.3 is --H or Cl;
[1239] R.sub.4 is --H or a C.sub.1-C.sub.10 straight chain
alkyl;
[1240] R.sub.5 is a C.sub.1-C.sub.4 straight or branched chain
alkyl or --C.sub.6H.sub.5;
[1241] R.sub.6 is a C.sub.1-C.sub.3 straight or branched chain
alkyl;
[1242] R.sub.7 is a C.sub.1-C.sub.3 straight or branched chain
alkyl; and
[1243] n is 1 to 5.
[1244] For use in the methods for inhibiting the replication or
infectivity of a virus, a preferred subclass of the compounds of
Formula (IX) are those wherein:
[1245] R.sub.1 is --H;
[1246] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5;
[1247] R.sub.3 is --H;
[1248] R.sub.4 is --H or a C.sub.1-C.sub.4 straight or branched
chain alkyl; and
[1249] n is 1 to 3.
[1250] For use in the methods for inhibiting the replication or
infectivity of a virus, a more preferred subclass of the compounds
of Formula (IX) are those wherein:
[1251] R.sub.1 is --H;
[1252] R.sub.2 is --CH.sub.3;
[1253] R.sub.3 is --H;
[1254] R.sub.4 is --C.sub.4H.sub.9; and
[1255] n is 1.
[1256] For use in the methods for inhibiting the replication or
infectivity of a virus, another more preferred subclass of the
compounds of Formula (IX) are those wherein:
[1257] R.sub.1 is --H;
[1258] R.sub.2 is --CH.sub.3;
[1259] R.sub.3 is --H;
[1260] R.sub.4 is --C.sub.2H.sub.5; and
[1261] n is 3.
[1262] The invention further provides methods for causing
immunosuppression in a patient comprising administering to a
patient in need thereof an effective amount of a compound of
Formula (IX) or a pharmaceutically acceptable salt thereof,
wherein, in the compound of Formula (IX):
[1263] R.sub.1 is --H, --CH.sub.3, --SO.sub.2-4-methylphenyl,
--CH.sub.2C.sub.6H.sub.5, --Si(R.sub.5R.sub.6R.sub.7),
--CH.sub.2OCH.sub.2CH.sub.2SiCH.sub.3, --C(O)OC(CH.sub.3).sub.3, or
--C(O)CH.sub.2C.sub.6H.sub.5;
[1264] R.sub.2 is --CH.sub.3, --CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub- .3, or --CH.sub.2C.sub.6H.sub.5;
[1265] R.sub.3 is --H or Cl;
[1266] R.sub.4 is --H or a C.sub.1-C.sub.10 straight chain
alkyl;
[1267] R.sub.5 is a C.sub.1-C.sub.4 straight or branched chain
alkyl or --C.sub.6H.sub.5;
[1268] R.sub.6 is a C.sub.1-C.sub.3 straight or branched chain
alkyl;
[1269] R.sub.7 is a C.sub.1-C.sub.3 straight or branched chain
alkyl; and
[1270] n is 1 to 5.
[1271] For use in the methods for causing immunosuppression, a
preferred subclass of the compounds of Formula (IX) are those
wherein:
[1272] R.sub.1 is --H;
[1273] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5;
[1274] R.sub.3 is --H;
[1275] R.sub.4 is --H or a C.sub.1-C.sub.4 straight or branched
chain alkyl; and
[1276] n is 1 to 3.
[1277] For use in the methods for causing immunosuppression, a more
preferred subclass of the compounds of Formula (IX) are those
wherein:
[1278] R.sub.1 is --H;
[1279] R.sub.2 is --CH.sub.3;
[1280] R.sub.3 is --H;
[1281] R.sub.4 is --C.sub.4H.sub.9; and
[1282] n is 1.
[1283] For use in the methods for causing immunosuppression,
another more preferred subclass of the compounds of Formula (IX)
are those wherein:
[1284] R.sub.1 is --H;
[1285] R.sub.2 is --CH.sub.3;
[1286] R.sub.3 is --H;
[1287] R.sub.4 is --C.sub.2H.sub.5; and
[1288] n is 3.
[1289] The invention further provides methods for treating or
preventing an autoimmune disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (IX) or a
pharmaceutically acceptable salt thereof, wherein, in the compound
of Formula (IX):
[1290] R.sub.1 is --H, --CH.sub.3, --SO.sub.2-4-methylphenyl,
--CH.sub.2C.sub.6H.sub.5, --Si(R.sub.5R.sub.6R.sub.7),
--CH.sub.2OCH.sub.2CH.sub.2SiCH.sub.3, --C(O)OC(CH.sub.3).sub.3, or
--C(O)CH.sub.2C.sub.6H.sub.5;
[1291] R.sub.2 is --CH.sub.3, --CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub- .3, or --CH.sub.2C.sub.6H.sub.5;
[1292] R.sub.3 is --H or Cl;
[1293] R.sub.4 is --H or a C.sub.1-C.sub.10 straight chain
alkyl;
[1294] R.sub.5 is a C.sub.1-C.sub.4 straight or branched chain
alkyl or --C.sub.6H.sub.5;
[1295] R.sub.6 is a C.sub.1-C.sub.3 straight or branched chain
alkyl;
[1296] R.sub.7 is a C.sub.1-C.sub.3 straight or branched chain
alkyl; and
[1297] n is 1 to 5.
[1298] For use in the methods for treating or preventing an
autoimmune disease, a preferred subclass of the compounds of
Formula (IX) are those wherein:
[1299] R.sub.1 is --H;
[1300] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5;
[1301] R.sub.3 is --H;
[1302] R.sub.4 is --H or a C.sub.1-C.sub.4 straight or branched
chain alkyl; and
[1303] n is 1 to 3.
[1304] For use in the methods for treating or preventing an
autoimmune disease, a more preferred subclass of the compounds of
Formula (IX) are those wherein:
[1305] R.sub.1 is --H;
[1306] R.sub.2 is --CH.sub.3;
[1307] R.sub.3 is --H;
[1308] R.sub.4 is --C.sub.4H.sub.9; and
[1309] n is 1.
[1310] For use in the methods for treating or preventing an
autoimmune disease, another more preferred subclass of the
compounds of Formula (IX) are those wherein:
[1311] R.sub.1 is --H;
[1312] R.sub.2 is --CH.sub.3;
[1313] R.sub.3 is --H;
[1314] R.sub.4 is --C.sub.2H.sub.5; and
[1315] n is 3.
5.10. Formula X
[1316] The present invention encompasses novel compounds having the
general Formula (X) and pharmaceutically acceptable salts thereof,
wherein:
[1317] R.sub.1 is --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--COCH.sub.3, --C(O)OC(CH.sub.3).sub.3, or
--C(O)CH.sub.2C.sub.6H.sub.5;
[1318] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5, the --CH.sub.2C.sub.6H.sub.5 being
unsubstituted or substituted with one or more halo, methoxyl,
methyl, methoxycarbonyl, or nitro groups;
[1319] R.sub.3 is --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5, or
--C(O)OC(CH.sub.3).sub.3;
[1320] R.sub.4 is --H or --CH.sub.3;
[1321] R.sub.5 is --H, --CH.sub.3, --OCH.sub.3, --F, --Cl, --Br,
--I, --CN, --NH.sub.2; --NH(C.sub.1-C.sub.3 straight or branched
chain alkyl), --NHCOCH.sub.3, --NO.sub.2, --COOH, --COOR.sub.6,
--OH, or --OCH.sub.2C.sub.6H.sub.5; and
[1322] R.sub.6 is a C.sub.1-C.sub.6 straight chain alkyl.
[1323] The compounds of Formula (X) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. The compounds of Formula (X) or a pharmaceutically
acceptable salt thereof are also useful for inhibiting the growth
of a cancer cell or neoplastic cell. The compounds of Formula (X)
or a pharmaceutically acceptable salt thereof are useful for
treating or preventing a viral infection in a patient in need of
such treatment or prevention. The compounds of Formula (X) or a
pharmaceutically acceptable salt thereof are also useful for
inhibiting the replication or infectivity of a virus. The compounds
of Formula (X) or a pharmaceutically acceptable salt thereof are
also useful for causing immunosuppression in a patient in need
thereof. The compounds of Formula (X) or a pharmaceutically
acceptable salt thereof are also useful for treating an autoimmune
disease in a patient in need of such treatment or prevention.
[1324] A preferred subclass of the compounds of Formula (X) is that
wherein:
[1325] R.sub.1 is --H;
[1326] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5;
[1327] R.sub.3 is --H;
[1328] R.sub.4 is --H or --CH.sub.3;
[1329] R.sub.5 is --H, halogen, or --COOR.sub.6; and
[1330] R.sub.6 is --CH.sub.3.
[1331] A more preferred subclass of the compounds of Formula (X) is
that wherein:
[1332] R.sub.1 is --H;
[1333] R.sub.2 is --CH.sub.3;
[1334] R.sub.3 is --H;
[1335] R.sub.4 is --H or --CH.sub.3; and
[1336] R.sub.5 is --H.
[1337] The present invention also provides compositions comprising
a pharmaceutically acceptable carrier and an effective amount of a
compound of Formula (X) or a pharmaceutically acceptable salt
thereof, wherein, in the compound of Formula (X):
[1338] R.sub.1 is --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--COCH.sub.3, --C(O)OC(CH.sub.3).sub.3, or
--C(O)CH.sub.2C.sub.6H.sub.5;
[1339] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5, the --CH.sub.2C.sub.6H.sub.5 being
unsubstituted or substituted with one or more halo, methoxyl,
methyl, methoxycarbonyl, or nitro groups;
[1340] R.sub.3 is --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5, or
--C(O)OC(CH.sub.3).sub.3;
[1341] R.sub.4 is --H or --CH.sub.3;
[1342] R.sub.5 is --H, --CH.sub.3, --OCH.sub.3, --F, --Cl, --Br,
--I, --CN, --NH.sub.2; --NH(C.sub.1-C.sub.3 straight or branched
chain alkyl), --NHCOCH.sub.3, --NO.sub.2, --COOH, --COOR.sub.6,
--OH, or --OCH.sub.2C.sub.6H.sub.5; and
[1343] R.sub.6 is a C.sub.1-C.sub.6 straight chain alkyl.
[1344] The compositions comprising a pharmaceutically acceptable
carrier and a compound of Formula (X) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. These compositions are also useful for inhibiting
the growth of a cancer cell or neoplastic cell. The compositions
comprising a pharmaceutically acceptable carrier and a compound of
Formula (X) or a pharmaceutically acceptable salt thereof are
useful for treating or preventing a viral infection in a patient in
need of such treatment or prevention. These compositions are also
useful for inhibiting the replication or infectivity of a virus.
The compositions comprising a pharmaceutically acceptable carrier
and a compound of Formula (X) or a pharmaceutically acceptable salt
thereof are also useful for causing immunosuppression in a patient
in need thereof. The compositions comprising a pharmaceutically
acceptable carrier and a compound of Formula (X) or a
pharmaceutically acceptable salt thereof are also useful for
treating an autoimmune disease in a patient in need of such
treatment or prevention.
[1345] A preferred subclass of the compositions comprising a
pharmaceutically acceptable carrier and a compound of Formula (X)
or a pharmaceutically acceptable salt thereof is that wherein, in
the compound of Formula (X):
[1346] R.sub.1 is --H;
[1347] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5;
[1348] R.sub.3 is --H;
[1349] R.sub.4 is --H or --CH.sub.3;
[1350] R.sub.5 is --H, halogen, or --COOR.sub.6; and
[1351] R.sub.6 is --CH.sub.3.
[1352] A more preferred subclass of the compositions comprising a
pharmaceutically acceptable carrier and a compound of Formula (X)
or a pharmaceutically acceptable salt thereof is that wherein, in
the compound of Formula (X):
[1353] R.sub.1 is --H;
[1354] R.sub.2 is --CH.sub.3;
[1355] R.sub.3 is --H;
[1356] R.sub.4 is --H or --CH.sub.3; and
[1357] R.sub.5 is --H.
[1358] The invention further provides methods for treating or
preventing cancer or neoplastic disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (X) or a
pharmaceutically acceptable salt thereof, wherein, in the compound
of Formula (X):
[1359] R.sub.1 is --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--COCH.sub.3, --C(O)OC(CH.sub.3).sub.3, or
--C(O)CH.sub.2C.sub.6H.sub.5;
[1360] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5, the --CH.sub.2C.sub.6H.sub.5 being
unsubstituted or substituted with one or more halo, methoxyl,
methyl, methoxycarbonyl, or nitro groups;
[1361] R.sub.3 is --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5, or
--C(O)OC(CH.sub.3).sub.3;
[1362] R.sub.4 is --H or --CH.sub.3;
[1363] R.sub.5 is --H, --CH.sub.3, --OCH.sub.3, --F, --Cl, --Br,
--I, --CN, --NH.sub.2; --NH(C.sub.1-C.sub.3 straight or branched
chain alkyl), --NHCOCH.sub.3, --NO.sub.2, --COOH, --COOR.sub.6,
--OH, or --OCH.sub.2C.sub.6H.sub.5; and
[1364] R.sub.6 is a C.sub.1-C.sub.6 straight chain alkyl.
[1365] For use in the methods for treating or preventing cancer or
neoplastic disease, a preferred subclass of the compounds of
Formula (X) is that wherein, in the compound of Formula (X):
[1366] R.sub.1 is --H;
[1367] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5;
[1368] R.sub.3 is --H;
[1369] R.sub.4 is --H or --CH.sub.3;
[1370] R.sub.5 is --H, halogen, or --COOR.sub.6; and
[1371] R.sub.6 is --CH.sub.3.
[1372] For use in the methods for treating or preventing cancer or
neoplastic disease, a more preferred subclass of the compounds of
Formula (X) is that wherein, in the compound of Formula (X):
[1373] R.sub.1 is --H;
[1374] R.sub.2 is --CH.sub.3;
[1375] R.sub.3 is --H;
[1376] R.sub.4 is --H or --CH.sub.3; and
[1377] R.sub.5 is --H.
[1378] The invention further provides methods for inhibiting the
growth of a cancer cell or neoplastic cell comprising contacting a
cancer cell or neoplastic cell with an effective amount of a
compound having the general Formula (X) or a pharmaceutically
acceptable salt thereof, wherein, in the compound of Formula
(X):
[1379] R.sub.1 is --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--COCH.sub.3, --C(O)OC(CH.sub.3).sub.3, or
--C(O)CH.sub.2C.sub.6H.sub.5;
[1380] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5, the --CH.sub.2C.sub.6H.sub.5 being
unsubstituted or substituted with one or more halo, methoxyl,
methyl, methoxycarbonyl, or nitro groups;
[1381] R.sub.3 is --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5, or
--C(O)OC(CH.sub.3).sub.3;
[1382] R.sub.4 is --H or --CH.sub.3;
[1383] R.sub.5 is --H, --CH.sub.3, --OCH.sub.3, --F, --Cl, --Br,
--I, --CN, --NH.sub.2; --NH(C.sub.1-C.sub.3 straight or branched
chain alkyl), --NHCOCH.sub.3, --NO.sub.2, --COOH, --COOR.sub.6,
--OH, or --OCH.sub.2C.sub.6H.sub.5; and
[1384] R.sub.6 is a C.sub.1-C.sub.6 straight chain alkyl.
[1385] For use in the methods for inhibiting the growth of a cancer
or neoplastic cell, a preferred subclass of the compounds of
Formula (X) is that wherein, in the compound of Formula (X):
[1386] R.sub.1 is --H;
[1387] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5;
[1388] R.sub.3 is --H;
[1389] R.sub.4 is --H or --CH.sub.3;
[1390] R.sub.5 is --H, halogen, or --COOR.sub.6; and
[1391] R.sub.6 is --CH.sub.3.
[1392] For use in the methods for inhibiting the growth of a cancer
or neoplastic cell, a more preferred subclass of the compounds of
Formula (X) is that wherein, in the compound of Formula (X):
[1393] R.sub.1 is --H;
[1394] R.sub.2 is --CH.sub.3;
[1395] R.sub.3 is --H;
[1396] R.sub.4 is --H or --CH.sub.3; and
[1397] R.sub.5 is --H.
[1398] The invention further provides methods for treating or
preventing a viral infection in a patient comprising administering
to a patient in need of such treatment or prevention an effective
amount of a compound of Formula (X) or a pharmaceutically
acceptable salt thereof, wherein, in the compound of Formula
(X):
[1399] R.sub.1 is --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--COCH.sub.3, --C(O)OC(CH.sub.3).sub.3, or
--C(O)CH.sub.2C.sub.6H.sub.5;
[1400] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5, the --CH.sub.2C.sub.6H.sub.5 being
unsubstituted or substituted with one or more halo, methoxyl,
methyl, methoxycarbonyl, or nitro groups;
[1401] R.sub.3 is --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5, or
--C(O)OC(CH.sub.3).sub.3;
[1402] R.sub.4 is --H or --CH.sub.3;
[1403] R.sub.5 is --H, --CH.sub.3, --OCH.sub.3, --F, --Cl, --Br,
--I, --CN, --NH.sub.2; --NH(C.sub.1-C.sub.3 straight or branched
chain alkyl), --NHCOCH.sub.3, --NO.sub.2, --COOH, --COOR.sub.6,
--OH, or --OCH.sub.2C.sub.6H.sub.5; and
[1404] R.sub.6 is a C.sub.1-C.sub.6 straight chain alkyl.
[1405] For use in the present methods for treating or preventing a
viral infection, a preferred subclass of the compounds of Formula
(X) is that wherein, in the compound of Formula (X):
[1406] R.sub.1 is --H;
[1407] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5;
[1408] R.sub.3 is --H;
[1409] R.sub.4 is --H or --CH.sub.3;
[1410] R.sub.5 is --H, halogen, or --COOR.sub.6; and
[1411] R.sub.6 is --CH.sub.3.
[1412] For use in the present methods for treating or preventing a
viral infection, a more preferred subclass of the compounds of
Formula (X) is that wherein, in the compound of Formula (X):
[1413] R.sub.1 is --H;
[1414] R.sub.2 is --CH.sub.3;
[1415] R.sub.3 is --H;
[1416] R.sub.4 is --H or --CH.sub.3; and
[1417] R.sub.5 is --H.
[1418] The invention further provides methods for inhibiting the
replication or infectivity of a virus comprising contacting a virus
or a virus-infected cell with an effective amount of a compound
having the general Formula (X) or a pharmaceutically acceptable
salt thereof, wherein, in the compound of Formula (X):
[1419] R.sub.1 is --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--COCH.sub.3, --C(O)OC(CH.sub.3).sub.3, or
--C(O)CH.sub.2C.sub.6H.sub.5;
[1420] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5, the --CH.sub.2C.sub.6H.sub.5 being
unsubstituted or substituted with one or more halo, methoxyl,
methyl, methoxycarbonyl, or nitro groups;
[1421] R.sub.3 is --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5, or
--C(O)OC(CH.sub.3).sub.3;
[1422] R.sub.4 is --H or --CH.sub.3;
[1423] R.sub.5 is --H, --CH.sub.3, --OCH.sub.3, --F, --Cl, --Br,
--I, --CN, --NH.sub.2; --NH(C.sub.1-C.sub.3 straight or branched
chain alkyl), --NHCOCH.sub.3, --NO.sub.2, --COOH, --COOR.sub.6,
--OH, or --OCH.sub.2C.sub.6H.sub.5; and
[1424] R.sub.6 is a C.sub.1-C.sub.6 straight chain alkyl.
[1425] For use in the methods for inhibiting the replication or
infectivity of a virus, a preferred subclass of the compounds of
Formula (X) are those wherein:
[1426] R.sub.1 is --H;
[1427] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5;
[1428] R.sub.3 is --H;
[1429] R.sub.4 is --H or --CH.sub.3;
[1430] R.sub.5 is --H, halogen, or --COOR.sub.6; and
[1431] R.sub.6 is --CH.sub.3.
[1432] For use in the methods for inhibiting the replication or
infectivity of a virus, a more preferred subclass of the compounds
of Formula (X) are those wherein:
[1433] R.sub.1 is --H;
[1434] R.sub.2 is --CH.sub.3;
[1435] R.sub.3 is --H;
[1436] R.sub.4 is --H or --CH.sub.3; and
[1437] R.sub.5 is --H.
[1438] The invention further provides methods for causing
immunosuppression in a patient comprising administering to a
patient in need thereof an effective amount of a compound of
Formula (X) or a pharmaceutically acceptable salt thereof, wherein,
in the compound of Formula (X):
[1439] R.sub.1 is --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--COCH.sub.3, --C(O)OC(CH.sub.3).sub.3, or
--C(O)CH.sub.2C.sub.6H.sub.5;
[1440] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5, the --CH.sub.2C.sub.6H.sub.5 being
unsubstituted or substituted with one or more halo, methoxyl,
methyl, methoxycarbonyl, or nitro groups;
[1441] R.sub.3 is --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5, or
--C(O)OC(CH.sub.3).sub.3;
[1442] R.sub.4 is --H or --CH.sub.3;
[1443] R.sub.5 is --H, --CH.sub.3, --OCH.sub.3, --F, --Cl, --Br,
--I, --CN, --NH.sub.2; --NH(C.sub.1-C.sub.3 straight or branched
chain alkyl), --NHCOCH.sub.3, --NO.sub.2, --COOH, --COOR.sub.6,
--OH, or --OCH.sub.2C.sub.6H.sub.5; and
[1444] R.sub.6 is a C.sub.1-C.sub.6 straight chain alkyl.
[1445] For use in the methods for causing immunosuppression, a
preferred subclass of the compounds of Formula (X) are those
wherein:
[1446] R.sub.1 is --H;
[1447] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5;
[1448] R.sub.3 is --H;
[1449] R.sub.4 is --H or --CH.sub.3;
[1450] R.sub.5 is --H, halogen, or --COOR.sub.6; and
[1451] R.sub.6 is --CH.sub.3.
[1452] For use in the methods for causing immunosuppression, a more
preferred subclass of the compounds of Formula (X) are those
wherein:
[1453] R.sub.1 is --H;
[1454] R.sub.2 is --CH.sub.3;
[1455] R.sub.3 is --H;
[1456] R.sub.4 is --H or --CH.sub.3; and
[1457] R.sub.5 is --H.
[1458] The invention further provides methods for treating or
preventing an autoimmune disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (X) or a
pharmaceutically acceptable salt thereof, wherein, in the compound
of Formula (X):
[1459] R.sub.1 is --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--COCH.sub.3, --C(O)OC(CH.sub.3).sub.3, or
--C(O)CH.sub.2C.sub.6H.sub.5;
[1460] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5, the --CH.sub.2C.sub.6H.sub.5 being
unsubstituted or substituted with one or more halo, methoxyl,
methyl, methoxycarbonyl, or nitro groups;
[1461] R.sub.3 is --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5, or
--C(O)OC(CH.sub.3).sub.3;
[1462] R.sub.4 is --H or --CH.sub.3;
[1463] R.sub.5 is --H, --CH.sub.3, --OCH.sub.3, --F, --Cl, --Br,
--I, --CN, --NH.sub.2; --NH(C.sub.1-C.sub.3 straight or branched
chain alkyl), --NHCOCH.sub.3, --NO.sub.2, --COOH, --COOR.sub.6,
--OH, or --OCH.sub.2C.sub.6H.sub.5; and
[1464] R.sub.6 is a C.sub.1-C.sub.6 straight chain alkyl.
[1465] For use in the methods for treating or preventing an
autoimmune disease, a preferred subclass of the compounds of
Formula (X) are those wherein:
[1466] R.sub.1 is --H;
[1467] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5;
[1468] R.sub.3 is --H;
[1469] R.sub.4 is --H or --CH.sub.3;
[1470] R.sub.5 is --H, halogen, or --COOR.sub.6; and
[1471] R.sub.6 is --CH.sub.3.
[1472] For use in the methods for treating or preventing an
autoimmune disease, a more preferred subclass of the compounds of
Formula (X) are those wherein:
[1473] R.sub.1 is --H;
[1474] R.sub.2 is --CH.sub.3;
[1475] R.sub.3 is --H;
[1476] R.sub.4 is --H or --CH.sub.3; and
[1477] R.sub.5 is --H.
5.11. Formula XI
[1478] The present invention encompasses novel compounds having the
general Formula (XI) and pharmaceutically acceptable salts thereof,
wherein:
[1479] R.sub.1 is --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--COCH.sub.3, --C(O)OC(CH.sub.3).sub.3, or
--C(O)CH.sub.2C.sub.6H.sub.5;
[1480] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5;
[1481] R.sub.3 is --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, or --C(O)CH.sub.2C.sub.6H.sub.5;
[1482] R.sub.4 is --H or --CH.sub.3;
[1483] R.sub.5 is --H, a C.sub.1-C.sub.10 straight chain alkyl,
--OR.sub.6, --F, --Cl, --Br, --I, --CN, --COOH, --COOR.sub.6,
--NH.sub.2; --NHCOR.sub.6, --NO.sub.2, --OH, or
--OCH.sub.2C.sub.6H.sub.5; and
[1484] R.sub.6 is a C.sub.1-C.sub.6 straight chain alkyl.
[1485] The compounds of Formula (XI) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. The compounds of Formula (XI) or a pharmaceutically
acceptable salt thereof are also useful for inhibiting the growth
of a cancer cell or neoplastic cell. The compounds of Formula (XI)
or a pharmaceutically acceptable salt thereof are useful for
treating or preventing a viral infection in a patient in need of
such treatment or prevention. The compounds of Formula (XI) or a
pharmaceutically acceptable salt thereof are also useful for
inhibiting the replication or infectivity of a virus. The compounds
of Formula (XI) or a pharmaceutically acceptable salt thereof are
also useful for causing immunosuppression in a patient in need
thereof. The compounds of Formula (XI) or a pharmaceutically
acceptable salt thereof are also useful for treating an autoimmune
disease in a patient in need of such treatment or prevention.
[1486] A preferred subclass of the compounds of Formula (XI) is
that wherein:
[1487] R.sub.1 is --H;
[1488] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5;
[1489] R.sub.3 is --H;
[1490] R.sub.4 is --H or --CH.sub.3;
[1491] R.sub.5 is --H, --CH.sub.3, halogen, or COOR.sub.6; and
[1492] R.sub.6 is --CH.sub.3.
[1493] A more preferred subclass of the compounds of Formula (XI)
is that wherein:
[1494] R.sub.1 is --H;
[1495] R.sub.2 is --CH.sub.3;
[1496] R.sub.3 is --H;
[1497] R.sub.4 is --CH.sub.3; and
[1498] R.sub.5 is --H or Cl.
[1499] The present invention also provides compositions comprising
a pharmaceutically acceptable carrier and an effective amount of a
compound of Formula (XI) or a pharmaceutically acceptable salt
thereof, wherein, in the compound of Formula (XI):
[1500] R.sub.1 is --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--COCH.sub.3, --C(O)OC(CH.sub.3).sub.3, or
--C(O)CH.sub.2C.sub.6H.sub.5;
[1501] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5;
[1502] R.sub.3 is --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, or --C(O)CH.sub.2C.sub.6H.sub.5;
[1503] R.sub.4 is --H or --CH.sub.3;
[1504] R.sub.5 is --H, a C.sub.1-C.sub.10 straight chain alkyl,
--OR.sub.6, --F, --Cl, --Br, --I, --CN, --COOH, --COOR.sub.6,
--NH.sub.2; --NHCOR.sub.6, --NO.sub.2, --OH, or
--OCH.sub.2C.sub.6H.sub.5; and
[1505] R.sub.6 is a C.sub.1-C.sub.6 straight chain alkyl.
[1506] The compositions comprising a pharmaceutically acceptable
carrier and a compound of Formula (XI) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. These compositions are also useful for inhibiting
the growth of a cancer cell or neoplastic cell. The compositions
comprising a pharmaceutically acceptable carrier and a compound of
Formula (XI) or a pharmaceutically acceptable salt thereof are
useful for treating or preventing a viral infection in a patient in
need of such treatment or prevention. These compositions are also
useful for inhibiting the replication or infectivity of a virus.
The compositions comprising a pharmaceutically acceptable carrier
and a compound of Formula (XI) or a pharmaceutically acceptable
salt thereof are also useful for causing immunosuppression in a
patient in need thereof. The compositions comprising a
pharmaceutically acceptable carrier and a compound of Formula (XI)
or a pharmaceutically acceptable salt thereof are also useful for
treating an autoimmune disease in a patient in need of such
treatment or prevention.
[1507] A preferred subclass of the compositions comprising a
pharmaceutically acceptable carrier and a compound of Formula (XI)
or a pharmaceutically acceptable salt thereof is that wherein, in
the compound of Formula (XI):
[1508] R.sub.1 is --H;
[1509] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5;
[1510] R.sub.3 is --H;
[1511] R.sub.4 is --H or --CH.sub.3;
[1512] R.sub.5 is --H, --CH.sub.3, halogen, or COOR.sub.6; and
[1513] R.sub.6 is --CH.sub.3.
[1514] A more preferred subclass of the compositions comprising a
pharmaceutically acceptable carrier and a compound of Formula (XI)
or a pharmaceutically acceptable salt thereof is that wherein, in
the compound of Formula (XI):
[1515] R.sub.1 is --H;
[1516] R.sub.2 is --CH.sub.3;
[1517] R.sub.3 is --H;
[1518] R.sub.4 is --CH.sub.3; and
[1519] R.sub.5 is --H or Cl.
[1520] The invention further provides methods for treating or
preventing cancer or neoplastic disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (XI) or a
pharmaceutically acceptable salt thereof, wherein, in the compound
of Formula (XI):
[1521] R.sub.1 is --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--COCH.sub.3, --C(O)OC(CH.sub.3).sub.3, or
--C(O)CH.sub.2C.sub.6H.sub.5;
[1522] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5;
[1523] R.sub.3 is --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, or --C(O)CH.sub.2C.sub.6H.sub.5;
[1524] R.sub.4 is --H or --CH.sub.3;
[1525] R.sub.5 is --H, a C.sub.1-C.sub.10 straight chain alkyl,
--OR.sub.6, --F, --Cl, --Br, --I, --CN, --COOH, --COOR.sub.6,
--NH.sub.2; --NHCOR.sub.6, --NO.sub.2, --OH, or
--OCH.sub.2C.sub.6H.sub.5; and
[1526] R.sub.6 is a C.sub.1-C.sub.6 straight chain alkyl.
[1527] For use in the methods for treating or preventing cancer or
neoplastic disease, a preferred subclass of the compounds of
Formula (XI) is that wherein, in the compound of Formula (XI):
[1528] R.sub.1 is --H;
[1529] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5;
[1530] R.sub.3 is --H;
[1531] R.sub.4 is --H or --CH.sub.3;
[1532] R.sub.5 is --H, --CH.sub.3, halogen, or COOR.sub.6; and
[1533] R.sub.6 is --CH.sub.3.
[1534] For use in the methods for treating or preventing cancer or
neoplastic disease, a more preferred subclass of the compounds of
Formula (XI) is that wherein, in the compound of Formula (XI):
[1535] R.sub.1 is --H;
[1536] R.sub.2 is --CH.sub.3;
[1537] R.sub.3 is --H;
[1538] R.sub.4 is --CH.sub.3; and
[1539] R.sub.5 is --H or Cl.
[1540] The invention further provides methods for inhibiting the
growth of a cancer cell or neoplastic cell comprising a contacting
a cancer cell or neoplastic cell with an effective amount of a
compound having the general Formula (XI) or a pharmaceutically
acceptable salt thereof, wherein, in the compound of Formula
(XI):
[1541] R.sub.1 is --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--COCH.sub.3, --C(O)OC(CH.sub.3).sub.3, or
--C(O)CH.sub.2C.sub.6H.sub.5;
[1542] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5;
[1543] R.sub.3 is --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, or --C(O)CH.sub.2C.sub.6H.sub.5;
[1544] R.sub.4 is --H or --CH.sub.3;
[1545] R.sub.5 is --H, a C.sub.1-C.sub.10 straight chain alkyl,
--OR.sub.6, --F, --Cl, --Br, --I, --CN, --COOH, --COOR.sub.6,
--NH.sub.2; --NHCOR.sub.6, --NO.sub.2, --OH, or
--OCH.sub.2C.sub.6H.sub.5; and
[1546] R.sub.6 is a C.sub.1-C.sub.6 straight chain alkyl.
[1547] For use in the methods for inhibiting the growth of a cancer
or neoplastic cell, a preferred subclass of the compounds of
Formula (XI) is that wherein, in the compound of Formula (XI):
[1548] R.sub.1 is --H;
[1549] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5;
[1550] R.sub.3 is --H;
[1551] R.sub.4 is --H or --CH.sub.3;
[1552] R.sub.5 is --H, --CH.sub.3, halogen, or COOR.sub.6; and
[1553] R.sub.6 is --CH.sub.3.
[1554] For use in the methods for inhibiting the growth of a cancer
or neoplastic cell, a more preferred subclass of the compounds of
Formula (XI) is that wherein, in the compound of Formula (XI):
[1555] R.sub.1 is --H;
[1556] R.sub.2 is --CH.sub.3;
[1557] R.sub.3 is --H;
[1558] R.sub.4 is --CH.sub.3; and
[1559] R.sub.5 is --H or Cl.
[1560] The invention further provides methods for treating or
preventing a viral infection in a patient comprising administering
to a patient in need of such treatment or prevention an effective
amount of a compound of Formula (XI) or a pharmaceutically
acceptable salt thereof, wherein, in the compound of Formula
(XI):
[1561] R.sub.1 is --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--COCH.sub.3, --C(O)OC(CH.sub.3).sub.3, or
--C(O)CH.sub.2C.sub.6H.sub.5;
[1562] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5;
[1563] R.sub.3 is --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, or --C(O)CH.sub.2C.sub.6H.sub.5;
[1564] R.sub.4 is --H or --CH.sub.3;
[1565] R.sub.5 is --H, a C.sub.1-C.sub.10 straight chain alkyl,
--OR.sub.6, --F, --Cl, --Br, --I, --CN, --COOH, --COOR.sub.6,
--NH.sub.2; --NHCOR.sub.6, --NO.sub.2, --OH, or
--OCH.sub.2C.sub.6H.sub.5; and
[1566] R.sub.6 is a C.sub.1-C.sub.6 straight chain alkyl.
[1567] For use in the present methods for treating or preventing a
viral infection, a preferred subclass of the compounds of Formula
(XI) is that wherein, in the compound of Formula (XI):
[1568] R.sub.1 is --H;
[1569] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5;
[1570] R.sub.3 is --H;
[1571] R.sub.4 is --H or --CH.sub.3;
[1572] R.sub.5 is --H, --CH.sub.3, halogen, or COOR.sub.6; and
[1573] R.sub.6 is --CH.sub.3.
[1574] For use in the present methods for treating or preventing a
viral infection, a more preferred subclass of the compounds of
Formula (XI) is that wherein, in the compound of Formula (XI):
[1575] R.sub.1 is --H;
[1576] R.sub.2 is --CH.sub.3;
[1577] R.sub.3 is --H;
[1578] R.sub.4 is --CH.sub.3; and
[1579] R.sub.5 is --H or Cl.
[1580] The invention further provides methods for inhibiting the
replication or infectivity of a virus comprising a contacting a
virus or a virus-infected cell with an effective amount of a
compound having the general Formula (XI) or a pharmaceutically
acceptable salt thereof, wherein, in the compound of Formula
(XI):
[1581] R.sub.1 is --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--COCH.sub.3, --C(O)OC(CH.sub.3).sub.3, or
--C(O)CH.sub.2C.sub.6H.sub.5;
[1582] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5;
[1583] R.sub.3 is --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, or --C(O)CH.sub.2C.sub.6H.sub.5;
[1584] R.sub.4 is --H or --CH.sub.3;
[1585] R.sub.5 is --H, a C.sub.1-C.sub.10 straight chain alkyl,
--OR.sub.6, --F, --Cl, --Br, --I, --CN, --COOH, --COOR.sub.6,
--NH.sub.2; --NHCOR.sub.6, --NO.sub.2, --OH, or
--OCH.sub.2C.sub.6H.sub.5; and
[1586] R.sub.6 is a C.sub.1-C.sub.6 straight chain alkyl.
[1587] For use in the methods for inhibiting the replication or
infectivity of a virus, a preferred subclass of the compounds of
Formula (XI) are those wherein:
[1588] R.sub.1 is --H;
[1589] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5;
[1590] R.sub.3 is --H;
[1591] R.sub.4 is --H or --CH.sub.3;
[1592] R.sub.5 is --H, --CH.sub.3, halogen, or COOR.sub.6; and
[1593] R.sub.6 is --CH.sub.3.
[1594] For use in the methods for inhibiting the replication or
infectivity of a virus, a more preferred subclass of the compounds
of Formula (XI) are those wherein:
[1595] R.sub.1 is --H;
[1596] R.sub.2 is --CH.sub.3;
[1597] R.sub.3 is --H;
[1598] R.sub.4 is --CH.sub.3; and
[1599] R.sub.5 is --H or Cl.
[1600] The invention further provides methods for causing
immunosuppression in a patient comprising administering to a
patient in need thereof an effective amount of a compound of
Formula (XI) or a pharmaceutically acceptable salt thereof,
wherein, in the compound of Formula (XI):
[1601] R.sub.1 is --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--COCH.sub.3, --C(O)OC(CH.sub.3).sub.3, or
--C(O)CH.sub.2C.sub.6H.sub.5;
[1602] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5;
[1603] R.sub.3 is --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, or --C(O)CH.sub.2C.sub.6H.sub.5;
[1604] R.sub.4 is --H or --CH.sub.3;
[1605] R.sub.5 is --H, a C.sub.1-C.sub.10 straight chain alkyl,
--OR.sub.6, --F, --Cl, --Br, --I, --CN, --COOH, --COOR.sub.6,
--NH.sub.2; --NHCOR.sub.6, --NO.sub.2, --OH, or
--OCH.sub.2C.sub.6H.sub.5; and
[1606] R.sub.6 is a C.sub.1-C.sub.6 straight chain alkyl.
[1607] For use in the methods for causing immunosuppression, a
preferred subclass of the compounds of Formula (XI) are those
wherein:
[1608] R.sub.1 is --H;
[1609] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5;
[1610] R.sub.3 is --H;
[1611] R.sub.4 is --H or --CH.sub.3;
[1612] R.sub.5 is --H, --CH.sub.3, halogen, or COOR.sub.6; and
[1613] R.sub.6 is --CH.sub.3.
[1614] For use in the methods for causing immunosuppression, a more
preferred subclass of the compounds of Formula (XI) are those
wherein:
[1615] R.sub.1 is --H;
[1616] R.sub.2 is --CH.sub.3;
[1617] R.sub.3 is --H;
[1618] R.sub.4 is --CH.sub.3; and
[1619] R.sub.5 is --H or Cl.
[1620] The invention further provides methods for treating or
preventing an autoimmune disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (XI) or a
pharmaceutically acceptable salt thereof, wherein, in the compound
of Formula (XI):
[1621] R.sub.1 is --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--COCH.sub.3, --C(O)OC(CH.sub.3).sub.3, or
--C(O)CH.sub.2C.sub.6H.sub.5;
[1622] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5;
[1623] R.sub.3 is --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, or --C(O)CH.sub.2C.sub.6H.sub.5;
[1624] R.sub.4 is --H or --CH.sub.3;
[1625] R.sub.5 is --H, a C.sub.1-C.sub.10 straight chain alkyl,
--OR.sub.6, --F, --Cl, --Br, --I, --CN, --COOH, --COOR.sub.6,
--NH.sub.2; --NHCOR.sub.6, --NO.sub.2, --OH, or
--OCH.sub.2C.sub.6H.sub.5; and
[1626] R.sub.6 is a C.sub.1-C.sub.6 straight chain alkyl.
[1627] For use in the methods for treating or preventing an
autoimmune disease, a preferred subclass of the compounds of
Formula (XI) are those wherein:
[1628] R.sub.1 is --H;
[1629] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5;
[1630] R.sub.3 is --H;
[1631] R.sub.4 is --H or --CH.sub.3;
[1632] R.sub.5 is --H, --CH.sub.3, halogen, or COOR.sub.6; and
[1633] R.sub.6 is --CH.sub.3.
[1634] For use in the methods for treating or preventing an
autoimmune disease, a more preferred subclass of the compounds of
Formula (XI) are those wherein:
[1635] R.sub.1 is --H;
[1636] R.sub.2 is --CH.sub.3;
[1637] R.sub.3 is --H;
[1638] R.sub.4 is --CH.sub.3; and
[1639] R.sub.5 is --H or Cl.
5.12. Formula XII
[1640] The present invention encompasses novel compounds having the
general Formula (XII) or a pharmaceutically acceptable salt
thereof, wherein:
[1641] R.sub.1 is --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5, or
--C(O)OC(CH.sub.3).sub.3;
[1642] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5;
[1643] R.sub.3 is --H, --SO.sub.2CH.sub.3,
--SO.sub.2C.sub.6H.sub.5, --C(O)OC(CH.sub.3).sub.3, --COCH.sub.3,
--CO(CH.sub.2).sub.4CH.sub.3, --CO(CH.sub.2).sub.8CH.sub.3,
--COC.sub.6H.sub.5, --CO-4-(NHCOC.sub.6H.su- b.5)C.sub.6H.sub.4,
--CO-2-pyridyl, --CO-2-napthyl, --CO-2-quinolyl,
--CO-6-(NHCO(CH.sub.2).sub.4CH.sub.3)-2-quinolyl, --CO-2-pyrrolyl,
-2-CO-2-indolyl, --CO-1-methyl-2-indolyl, --CO-2-benzofuranyl,
--CO-2-benzothiophenyl, --CO-3-methyl-2-indenyl, or
--CO--R.sub.4-2-indolyl; and
[1644] R.sub.4 is -5-OCH.sub.3, -6-OH-7-OCH.sub.3, -5-NHCONH.sub.2,
5-NHCOC.sub.6H.sub.5, -5-NHCO-indolyl, -5-NHCO-2-benzofuranyl,
-5-NHCO-5(NHCONH.sub.2)-2-indolyl, or
-5-NHCO-5-(NHCOC.sub.6H.sub.5)-2-in- dolyl.
[1645] The compounds of Formula (XII) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. The compounds of Formula (XII) or a pharmaceutically
acceptable salt thereof are also useful for inhibiting the growth
of a cancer cell or neoplastic cell. The compounds of Formula (XII)
or a pharmaceutically acceptable salt thereof are useful for
treating or preventing a viral infection in a patient in need of
such treatment or prevention. The compounds of Formula (XII) or a
pharmaceutically acceptable salt thereof are also useful for
inhibiting the replication or infectivity of a virus. The compounds
of Formula (XII) or a pharmaceutically acceptable salt thereof are
also useful for causing immunosuppression in a patient in need
thereof. The compounds of Formula (XII) or a pharmaceutically
acceptable salt thereof are also useful for treating an autoimmune
disease in a patient in need of such treatment or prevention.
[1646] A preferred subclass of the compounds of Formula (XII) is
that wherein:
[1647] R.sub.1 is --H;
[1648] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5;
[1649] R.sub.3 is --H, --COCH.sub.3, --CO-2-quinolyl,
--CO-6-(NHCO(CH.sub.2).sub.4CH.sub.3)-2-quinolyl, -2--CO-2-indolyl,
or --CO--R.sub.4-2-indolyl; and
[1650] R.sub.4 is -5-NHCO-indolyl, -5-NHCO-2-benzofuranyl, or
-5-NHCO-5(NHCONH.sub.2)-2-indolyl.
[1651] A more preferred subclass of the compounds of Formula (XII)
is that wherein:
[1652] R.sub.1 is --H;
[1653] R.sub.2 is --CH.sub.3;
[1654] R.sub.3 is --H, --COCH.sub.3, or --CO--R.sub.4-2-indolyl;
and;
[1655] R.sub.4 is -5-NHCO-indolyl.
[1656] The present invention also provides compositions comprising
a pharmaceutically acceptable carrier and an effective amount of a
compound of Formula (XII) or a pharmaceutically acceptable salt
thereof, wherein, in the compound of Formula (XII):
[1657] R.sub.1 is --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5, or
--C(O)OC(CH.sub.3).sub.3;
[1658] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5;
[1659] R.sub.3 is --H, --SO.sub.2CH.sub.3,
--SO.sub.2C.sub.6H.sub.5, --C(O)OC(CH.sub.3).sub.3, --COCH.sub.3,
--CO(CH.sub.2).sub.4CH.sub.3, --CO(CH.sub.2).sub.8CH.sub.3,
--COC.sub.6H.sub.5, --CO-4-(NHCOC.sub.6H.su- b.5)C.sub.6H.sub.4,
--CO-2-pyridyl, --CO-2-napthyl, --CO-2-quinolyl,
--CO-6-(NHCO(CH.sub.2).sub.4CH.sub.3)-2-quinolyl, --CO-2-pyrrolyl,
-2-CO-2-indolyl, --CO-1-methyl-2-indolyl, --CO-2-benzofuranyl,
--CO-2-benzothiophenyl, --CO-3-methyl-2-indenyl, or
--CO--R.sub.4-2-indolyl; and
[1660] R.sub.4 is -5-OCH.sub.3, -6-OH-7-OCH.sub.3, -5-NHCONH.sub.2,
5-NHCOC.sub.6H.sub.5, -5-NHCO-indolyl, -5-NHCO-2-benzofuranyl,
-5-NHCO-5-(NHCONH.sub.2)-2-indolyl, or
-5-NHCO-5-(NHCOC.sub.6H.sub.5)-2-i- ndolyl.
[1661] The compositions comprising a pharmaceutically acceptable
carrier and a compound of Formula (XII) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. These compositions are also useful for inhibiting
the growth of a cancer cell or neoplastic cell. The compositions
comprising a pharmaceutically acceptable carrier and a compound of
Formula (XII) or a pharmaceutically acceptable salt thereof are
useful for treating or preventing a viral infection in a patient in
need of such treatment or prevention. These compositions are also
useful for inhibiting the replication or infectivity of a virus.
The compositions comprising a pharmaceutically acceptable carrier
and a compound of Formula (XII) or a pharmaceutically acceptable
salt thereof are also useful for causing immunosuppression in a
patient in need thereof. The compositions comprising a
pharmaceutically acceptable carrier and a compound of Formula (XII)
or a pharmaceutically acceptable salt thereof are also useful for
treating an autoimmune disease in a patient in need of such
treatment or prevention.
[1662] A preferred subclass of the compositions comprising a
pharmaceutically acceptable carrier and a compound of Formula (XII)
or a pharmaceutically acceptable salt thereof is that wherein, in
the compound of Formula (XII):
[1663] R.sub.1 is --H;
[1664] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5;
[1665] R.sub.3 is --H, --COCH.sub.3, --CO-2-quinolyl,
--CO-6-(NHCO(CH.sub.2).sub.4CH.sub.3)-2-quinolyl, -2-CO-2-indolyl,
or --CO--R.sub.4-2-indolyl; and
[1666] R.sub.4 is -5-NHCO-indolyl, -5-NHCO-2-benzofuranyl, or
-5-NHCO-5(NHCONH.sub.2)-2-indolyl.
[1667] A more preferred subclass of the compositions comprising a
pharmaceutically acceptable carrier and a compound of Formula (XII)
or a pharmaceutically acceptable salt thereof is that wherein, in
the compound of Formula (XII):
[1668] R.sub.1 is --H;
[1669] R.sub.2 is --CH.sub.3;
[1670] R.sub.3 is --H, --COCH.sub.3, or --CO--R.sub.4-2-indolyl;
and;
[1671] R.sub.4 is -5-NHCO-indolyl.
[1672] The invention further provides methods for treating or
preventing cancer or neoplastic disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (XII) or a
pharmaceutically acceptable salt thereof, wherein, in the compound
of Formula (XII):
[1673] R.sub.1 is --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5, or
--C(O)OC(CH.sub.3).sub.3;
[1674] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5;
[1675] R.sub.3 is --H, --SO.sub.2CH.sub.3,
--SO.sub.2C.sub.6H.sub.5, --C(O)OC(CH.sub.3).sub.3, --COCH.sub.3,
--CO(CH.sub.2).sub.4CH.sub.3, --CO(CH.sub.2).sub.8CH.sub.3,
--COC.sub.6H.sub.5, --CO-4-(NHCOC.sub.6H.su- b.5)C.sub.6H.sub.4,
--CO-2-pyridyl, --CO-2-napthyl, --CO-2-quinolyl,
--CO-6-(NHCO(CH.sub.2).sub.4CH.sub.3)-2-quinolyl, --CO-2-pyrrolyl,
-2-CO-2-indolyl, --CO-1-methyl-2-indolyl, --CO-2-benzofuranyl,
--CO-2-benzothiophenyl, --CO-3-methyl-2-indenyl, or
--CO--R.sub.4-2-indolyl; and
[1676] R.sub.4 is -5-OCH.sub.3, -6-OH-7-OCH.sub.3, -5-NHCONH.sub.2,
5-NHCOC.sub.6H.sub.5, -5-NHCO-indolyl, -5-NHCO-2-benzofuranyl,
-5-NHCO-5(NHCONH.sub.2)-2-indolyl, or
-5-NHCO-5-(NHCOC.sub.6H.sub.5)-2-in- dolyl.
[1677] For use in the methods for treating or preventing cancer or
neoplastic disease, a preferred subclass of the compounds of
Formula (XII) is that wherein, in the compound of Formula
(XII):
[1678] R.sub.1 is --H;
[1679] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5;
[1680] R.sub.3 is --H, --COCH.sub.3, --CO-2-quinolyl,
--CO-6-(NHCO(CH.sub.2).sub.4CH.sub.3)-2-quinolyl, -2-CO-2-indolyl,
or --CO--R.sub.4-2-indolyl; and
[1681] R.sub.4 is -5-NHCO-indolyl, -5-NHCO-2-benzofuranyl, or
-5-NHCO-5(NHCONH.sub.2)-2-indolyl.
[1682] For use in the methods for treating or preventing cancer or
neoplastic disease, a more preferred subclass of the compounds of
Formula (XII) is that wherein, in the compound of Formula
(XII):
[1683] R.sub.1 is --H;
[1684] R.sub.2 is --CH.sub.3;
[1685] R.sub.3 is --H, --COCH.sub.3, or --CO--R.sub.4-2-indolyl;
and;
[1686] R.sub.4 is -5-NHCO-indolyl.
[1687] The invention further provides methods for inhibiting the
growth of a cancer cell or neoplastic cell comprising contacting a
cancer cell or neoplastic cell with an effective amount of a
compound having the general Formula (XII) or a pharmaceutically
acceptable salt thereof, wherein, in the compound of Formula
(XII):
[1688] R.sub.1 is --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5, or
--C(O)OC(CH.sub.3).sub.3;
[1689] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5;
[1690] R.sub.3 is --H, --SO.sub.2CH.sub.3,
--SO.sub.2C.sub.6H.sub.5, --C(O)OC(CH.sub.3).sub.3, --COCH.sub.3,
--CO(CH.sub.2).sub.4CH.sub.3, --CO(CH.sub.2).sub.8CH.sub.3,
--COC.sub.6H.sub.5, --CO-4-(NHCOC.sub.6H.su- b.5)C.sub.6H.sub.4,
--CO-2-pyridyl, --CO-2-napthyl, --CO-2-quinolyl,
--CO-6-(NHCO(CH.sub.2).sub.4CH.sub.3)-2-quinolyl, --CO-2-pyrrolyl,
-2-CO-2-indolyl, --CO-1-methyl-2-indolyl, --CO-2-benzofuranyl,
--CO-2-benzothiophenyl, --CO-3-methyl-2-indenyl, or
--CO--R.sub.4-2-indolyl; and
[1691] R.sub.4 is -5-OCH.sub.3, -6-OH-7-OCH.sub.3, -5-NHCONH.sub.2,
5-NHCOC.sub.6H.sub.5, -5-NHCO-indolyl, -5-NHCO-2-benzofuranyl,
-5-NHCO-5(NHCONH.sub.2)-2-indolyl, or
-5-NHCO-5-(NHCOC.sub.6H.sub.5)-2-in- dolyl.
[1692] For use in the methods for inhibiting the growth of a cancer
or neoplastic cell, a preferred subclass of the compounds of
Formula (XII) is that wherein, in the compound of Formula
(XII):
[1693] R.sub.1 is --H;
[1694] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5;
[1695] R.sub.3 is --H, --COCH.sub.3, --CO-2-quinolyl,
--CO-6-(NHCO(CH.sub.2 4CH.sub.3)-2-quinolyl, -2-CO-2-indolyl, or
--CO--R.sub.4-2-indolyl; and
[1696] R.sub.4 is -5-NHCO-indolyl, -5-NHCO-2-benzofuranyl, or
-5-NHCO-5(NHCONH.sub.2)-2-indolyl.
[1697] For use in the methods for inhibiting the growth of a cancer
or neoplastic cell, a more preferred subclass of the compounds of
Formula (XII) is that wherein, in the compound of Formula
(XII):
[1698] R.sub.1 is --H;
[1699] R.sub.2 is --CH.sub.3;
[1700] R.sub.3 is --H, --COCH.sub.3, or --CO--R.sub.4-2-indolyl;
and;
[1701] R.sub.4 is -5-NHCO-indolyl.
[1702] The invention further provides methods for treating or
preventing a viral infection in a patient comprising administering
to a patient in need of such treatment or prevention an effective
amount of a compound of Formula (XII) or a pharmaceutically
acceptable salt thereof, wherein, in the compound of Formula
(XII):
[1703] R.sub.1 is --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5, or
--C(O)OC(CH.sub.3).sub.3;
[1704] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5;
[1705] R.sub.3 is --H, --SO.sub.2CH.sub.3,
--SO.sub.2C.sub.6H.sub.5, --C(O)OC(CH.sub.3).sub.3, --COCH.sub.3,
--CO(CH.sub.2).sub.4CH.sub.3, --CO(CH.sub.2).sub.8CH.sub.3,
--COC.sub.6H.sub.5, --CO-4-(NHCOC.sub.6H.su- b.5)C.sub.6H.sub.4,
--CO-2-pyridyl, --CO-2-napthyl, --CO-2-quinolyl,
--CO-6-(NHCO(CH.sub.2).sub.4CH.sub.3)-2-quinolyl, --CO-2-pyrrolyl,
-2-CO-2-indolyl, --CO-1-methyl-2-indolyl, --CO-2-benzofuranyl,
--CO-2-benzothiophenyl, --CO-3-methyl-2-indenyl, or
--CO--R.sub.4-2-indolyl; and
[1706] R.sub.4 is -5-OCH.sub.3, -6-OH-7-OCH.sub.3, -5-NHCONH.sub.2,
5-NHCOC.sub.6H.sub.5, -5-NHCO-indolyl, -5-NHCO-2-benzofuranyl,
-5-NHCO-5(NHCONH.sub.2)-2-indolyl, or
-5-NHCO-5-(NHCOC.sub.6H.sub.5)-2-in- dolyl.
[1707] For use in the present methods for treating or preventing a
viral infection, a preferred subclass of the compounds of Formula
(XII) is that wherein, in the compound of Formula (XII):
[1708] R.sub.1 is --H;
[1709] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5;
[1710] R.sub.3 is --H, --COCH.sub.3, --CO-2-quinolyl,
--CO-6-(NHCO(CH.sub.2 4CH.sub.3)-2-quinolyl, -2-CO-2-indolyl, or
--CO--R.sub.4-2-indolyl; and
[1711] R.sub.4 is -5-NHCO-indolyl, -5-NHCO-2-benzofuranyl, or
-5-NHCO-5(NHCONH.sub.2)-2-indolyl.
[1712] For use in the present methods for treating or preventing a
viral infection, a more preferred subclass of the compounds of
Formula (XII) is that wherein, in the compound of Formula
(XIII):
[1713] R.sub.1 is --H;
[1714] R.sub.2 is --CH.sub.3;
[1715] R.sub.3 is --H, --COCH.sub.3, or --CO--R.sub.4-2-indolyl;
and;
[1716] R.sub.4 is -5-NHCO-indolyl.
[1717] The invention further provides methods for inhibiting the
replication or infectivity of a virus comprising contacting a virus
or a virus-infected cell with an effective amount of a compound
having the general Formula (XII) or a pharmaceutically acceptable
salt thereof, wherein, in the compound of Formula (XII):
[1718] R.sub.1 is --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5, or
--C(O)OC(CH.sub.3).sub.3;
[1719] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5;
[1720] R.sub.3 is --H, --SO.sub.2CH.sub.3,
--SO.sub.2C.sub.6H.sub.5, --C(O)OC(CH.sub.3).sub.3, --COCH.sub.3,
--CO(CH.sub.2).sub.4CH.sub.3, --CO(CH.sub.2).sub.8CH.sub.3,
--COC.sub.6H.sub.5, --CO-4-(NHCOC.sub.6H.su- b.5)C.sub.6H.sub.4,
--CO-2-pyridyl, --CO-2-napthyl, --CO-2-quinolyl,
--CO-6-(NHCO(CH.sub.2).sub.4CH.sub.3)-2-quinolyl, --CO-2-pyrrolyl,
-2-CO-2-indolyl, --CO-1-methyl-2-indolyl, --CO-2-benzofuranyl,
--CO-2-benzothiophenyl, --CO-3-methyl-2-indenyl, or
--CO--R.sub.4-2-indolyl; and
[1721] R.sub.4 is -5-OCH.sub.3, -6-OH-7-OCH.sub.3, -5-NHCONH.sub.2,
5-NHCOC.sub.6H.sub.5, -5-NHCO-indolyl, -5-NHCO-2-benzofuranyl,
-5-NHCO-5(NHCONH.sub.2)-2-indolyl, or
-5-NHCO-5-(NHCOC.sub.6H.sub.5)-2-in- dolyl.
[1722] For use in the methods for inhibiting the replication or
infectivity of a virus, a preferred subclass of the compounds of
Formula (XII) are those wherein:
[1723] R.sub.1 is --H;
[1724] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5;
[1725] R.sub.3 is --H, --COCH.sub.3, --CO-2-quinolyl,
--CO-6-(NHCO(CH.sub.2 4CH.sub.3)-2-quinolyl, -2-CO-2-indolyl, or
--CO--R.sub.4-2-indolyl; and
[1726] R.sub.4 is -5-NHCO-indolyl, -5-NHCO-2-benzofuranyl, or
-5-NHCO-5(NHCONH.sub.2)-2-indolyl.
[1727] For use in the methods for inhibiting the replication or
infectivity of a virus, a more preferred subclass of the compounds
of Formula (XII) are those wherein:
[1728] R.sub.1 is --H;
[1729] R.sub.2 is --CH.sub.3;
[1730] R.sub.3 is --H, --COCH.sub.3, or --CO--R.sub.4-2-indolyl;
and;
[1731] R.sub.4 is -5-NHCO-indolyl.
[1732] The invention further provides methods for causing
immunosuppression in a patient comprising administering to a
patient in need thereof an effective amount of a compound of
Formula (XII) or a pharmaceutically acceptable salt thereof,
wherein, in the compound of Formula (XII):
[1733] R.sub.1 is --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5, or
--C(O)OC(CH.sub.3).sub.3;
[1734] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5;
[1735] R.sub.3 is --H, --SO.sub.2CH.sub.3,
--SO.sub.2C.sub.6H.sub.5, --C(O)OC(CH.sub.3).sub.3, --COCH.sub.3,
--CO(CH.sub.2).sub.4CH.sub.3, --CO(CH.sub.2).sub.8CH.sub.3,
--COC.sub.6H.sub.5, --CO-4-(NHCOC.sub.6H.su- b.5)C.sub.6H.sub.4,
--CO-2-pyridyl, --CO-2-napthyl, --CO-2-quinolyl,
--CO-6-(NHCO(CH.sub.2).sub.4CH.sub.3)-2-quinolyl, --CO-2-pyrrolyl,
-2-CO-2-indolyl, --CO-1-methyl-2-indolyl, --CO-2-benzofuranyl,
--CO-2-benzothiophenyl, --CO-3-methyl-2-indenyl, or
--CO--R.sub.4-2-indolyl; and
[1736] R.sub.4 is -5-OCH.sub.3, -6-OH-7-OCH.sub.3, -5-NHCONH.sub.2,
5-NHCOC.sub.6H.sub.5, -5-NHCO-indolyl, -5-NHCO-2-benzofuranyl,
-5-NHCO-5(NHCONH.sub.2)-2-indolyl, or
-5-NHCO-5-(NHCOC.sub.6H.sub.5)-2-in- dolyl.
[1737] For use in the methods for causing immunosuppression, a
preferred subclass of the compounds of Formula (XII) are those
wherein:
[1738] R.sub.1 is --H;
[1739] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5;
[1740] R.sub.3 is --H, --COCH.sub.3, --CO-2-quinolyl,
--CO-6-(NHCO(CH.sub.2 4CH.sub.3)-2-quinolyl, -2-CO-2-indolyl, or
--CO--R.sub.4-2-indolyl; and
[1741] R.sub.4 is -5-NHCO-indolyl, -5-NHCO-2-benzofuranyl, or
-5-NHCO-5(NHCONH.sub.2)-2-indolyl.
[1742] For use in the methods for causing immunosuppression, a more
preferred subclass of the compounds of Formula (XII) are those
wherein:
[1743] R.sub.1 is --H;
[1744] R.sub.2 is --CH.sub.3;
[1745] R.sub.3 is --H, --COCH.sub.3, or --CO--R.sub.4-2-indolyl;
and;
[1746] R.sub.4 is -5-NHCO-indolyl.
[1747] The invention further provides methods for treating or
preventing an autoimmune disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (XII) or a
pharmaceutically acceptable salt thereof, wherein, in the compound
of Formula (XII):
[1748] R.sub.1 is --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5, or
--C(O)OC(CH.sub.3).sub.3;
[1749] R.sub.2 is a C.sub.1-C.sub.10 straight chain alkyl or
--CH.sub.2C.sub.6H.sub.5;
[1750] R.sub.3 is --H, --SO.sub.2CH.sub.3,
--SO.sub.2C.sub.6H.sub.5, --C(O)OC(CH.sub.3).sub.3, --COCH.sub.3,
--CO(CH.sub.2).sub.4CH.sub.3, --CO(CH.sub.2).sub.8CH.sub.3,
--COC.sub.6H.sub.5, --CO-4-(NHCOC.sub.6H.su- b.5)C.sub.6H.sub.4,
--CO-2-pyridyl, --CO-2-napthyl, --CO-2-quinolyl,
--CO-6-(NHCO(CH.sub.2).sub.4CH.sub.3)-2-quinolyl, --CO-2-pyrrolyl,
-2-CO-2-indolyl, --CO-1-methyl-2-indolyl, --CO-2-benzofuranyl,
--CO-2-benzothiophenyl, --CO-3-methyl-2-indenyl, or
--CO--R.sub.4-2-indolyl; and
[1751] R.sub.4 is -5-OCH.sub.3, -6-OH-7-OCH.sub.3, -5-NHCONH.sub.2,
5-NHCOC.sub.6H.sub.5, -5-NHCO-indolyl, -5-NHCO-2-benzofuranyl,
-5-NHCO-5(NHCONH.sub.2)-2-indolyl, or
-5-NHCO-5-(NHCOC.sub.6H.sub.5)-2-in- dolyl.
[1752] For use in the methods for treating or preventing an
autoimmune disease, a preferred subclass of the compounds of
Formula (XII) are those wherein:
[1753] R.sub.1 is --H;
[1754] R.sub.2 is --CH.sub.3 or --CH.sub.2C.sub.6H.sub.5;
[1755] R.sub.3 is --H, --COCH.sub.3, --CO-2-quinolyl,
--CO-6-(NHCO(CH.sub.2 4CH.sub.3)-2-quinolyl, -2-CO-2-indolyl, or
--CO--R.sub.4-2-indolyl; and
[1756] R.sub.4 is -5-NHCO-indolyl, -5-NHCO-2-benzofuranyl, or
-5-NHCO-5(NHCONH.sub.2)-2-indolyl.
[1757] For use in the methods treating or preventing an autoimmune
disease, a more preferred subclass of the compounds of Formula
(XII) are those wherein:
[1758] R.sub.1 is --H;
[1759] R.sub.2 is --CH.sub.3;
[1760] R.sub.3 is --H, --COCH.sub.3, or --CO--R.sub.4-2-indolyl;
and;
[1761] R.sub.4 is -5-NHCO-indolyl.
5.13. Formula XIII
[1762] The present invention encompasses novel compounds having the
general Formula (XIII) or a pharmaceutically acceptable salt
thereof, wherein:
[1763] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, or --C(O)OCH.sub.2C.sub.6H.sub.5;
[1764] R.sub.2 is --H or a C.sub.1-C.sub.10 straight chain alkyl;
and
[1765] n is 1 to 4.
[1766] The compounds of Formula (XIII) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. The compounds of Formula (XIII) or a
pharmaceutically acceptable salt thereof are also useful for
inhibiting the growth of a cancer cell or neoplastic cell. The
compounds of Formula (XIII) or a pharmaceutically acceptable salt
thereof are useful for treating or preventing a viral infection in
a patient in need of such treatment or prevention. The compounds of
Formula (XIII) or a pharmaceutically acceptable salt thereof are
also useful for inhibiting the replication or infectivity of a
virus. The compounds of Formula (XIII) or a pharmaceutically
acceptable salt thereof are also useful for causing
immunosuppression in a patient in need thereof. The compounds of
Formula (XII) or a pharmaceutically acceptable salt thereof are
also useful for treating an autoimmune disease in a patient in need
of such treatment or prevention.
[1767] A preferred subclass of the compounds of Formula (XIII) is
that wherein:
[1768] R.sub.1 is --H;
[1769] R.sub.2 is --H or --CH.sub.3; and
[1770] n is 1 to 4.
[1771] A more preferred subclass of the compounds of Formula (XIII)
is that wherein:
[1772] R.sub.1 is --H;
[1773] R.sub.2 is --H or --CH.sub.3; and
[1774] n is 2.
[1775] The present invention also provides compositions comprising
a pharmaceutically acceptable carrier and an effective amount of a
compound of Formula (XIII) or a pharmaceutically acceptable salt
thereof, wherein, in the compound of Formula (XIII):
[1776] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, or --C(O)OCH.sub.2C.sub.6H.sub.5;
[1777] R.sub.2 is --H or a C.sub.1-C.sub.10 straight chain alkyl;
and
[1778] n is 1 to 4.
[1779] The compositions comprising a pharmaceutically acceptable
carrier and a compound of Formula (XIII) or a pharmaceutically
acceptable salt thereof are useful for treating or preventing
cancer or neoplastic disease in a patient in need of such treatment
or prevention. These compositions are also useful for inhibiting
the growth of a cancer cell or neoplastic cell. The compositions
comprising a pharmaceutically acceptable carrier and a compound of
Formula (XIII) or a pharmaceutically acceptable salt thereof are
useful for treating or preventing a viral infection in a patient in
need of such treatment or prevention. These compositions are also
useful for inhibiting the replication or infectivity of a virus.
The compositions comprising a pharmaceutically acceptable carrier
and a compound of Formula (XIII) or a pharmaceutically acceptable
salt thereof are also useful for causing immunosuppression in a
patient in need thereof. The compositions comprising a
pharmaceutically acceptable carrier and a compound of Formula
(XIII) or a pharmaceutically acceptable salt thereof are also
useful for treating an autoimmune disease in a patient in need of
such treatment or prevention.
[1780] A preferred subclass of the compositions comprising a
pharmaceutically acceptable carrier and a compound of Formula
(XIII) or a pharmaceutically acceptable salt thereof is that
wherein, in the compound of Formula (XIII):
[1781] R.sub.1 is --H;
[1782] R.sub.2 is --H or --CH.sub.3; and
[1783] n is 1 to 4.
[1784] A more preferred subclass of the compositions comprising a
pharmaceutically acceptable carrier and a compound of Formula
(XIII) or a pharmaceutically acceptable salt thereof is that
wherein, in the compound of Formula (XIII):
[1785] R.sub.1 is --H;
[1786] R.sub.2 is --H or --CH.sub.3; and
[1787] n is 2.
[1788] The invention further provides methods for treating or
preventing cancer or neoplastic disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (XIII) or a
pharmaceutically acceptable salt thereof, wherein, in the compound
of Formula (XIII):
[1789] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, or --C(O)OCH.sub.2C.sub.6H.sub.5;
[1790] R.sub.2 is --H or a C.sub.1-C.sub.10 straight chain alkyl;
and
[1791] n is 1 to 4.
[1792] For use in the methods for treating or preventing cancer or
neoplastic disease, a preferred subclass of the compounds of
Formula (XIII) is that wherein, in the compound of Formula
(XIII):
[1793] R.sub.1 is --H;
[1794] R.sub.2 is --H or --CH.sub.3; and
[1795] n is 1 to 4.
[1796] For use in the methods for treating or preventing cancer or
neoplastic disease, a more preferred subclass of the compounds of
Formula (XIII) is that wherein, in the compound of Formula
(XIII):
[1797] R.sub.1 is --H;
[1798] R.sub.2 is --H or --CH.sub.3; and
[1799] n is 2.
[1800] The invention further provides methods for inhibiting the
growth of a cancer cell or neoplastic cell comprising contacting a
cancer cell or neoplastic cell with an effective amount of a
compound having the general Formula (XIII) or a pharmaceutically
acceptable salt thereof, wherein, in the compound of Formula
(XIII):
[1801] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, or --C(O)OCH.sub.2C.sub.6H.sub.5;
[1802] R.sub.2 is --H or a C.sub.1-C.sub.10 straight chain alkyl;
and
[1803] n is 1 to 4.
[1804] For use in the methods for inhibiting the growth of a cancer
or neoplastic cell, a preferred subclass of the compounds of
Formula (XIII) is that wherein, in the compound of Formula
(XIII):
[1805] R.sub.1 is --H;
[1806] R.sub.2 is --H or --CH.sub.3; and
[1807] n is 1 to 4.
[1808] For use in the methods for inhibiting the growth of a cancer
or neoplastic cell, a more preferred subclass of the compounds of
Formula (XIII) is that wherein, in the compound of Formula
(XIII):
[1809] R.sub.1 is --H;
[1810] R.sub.2 is --H or --CH.sub.3; and
[1811] n is 2.
[1812] The invention further provides methods for treating or
preventing a viral infection in a patient comprising administering
to a patient in need of such treatment or prevention an effective
amount of a compound of Formula (XIII) or a pharmaceutically
acceptable salt thereof, wherein, in the compound of Formula
(XIII):
[1813] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, or --C(O)OCH.sub.2C.sub.6H.sub.5;
[1814] R.sub.2 is --H or a C.sub.1-C.sub.10 straight chain alkyl;
and
[1815] n is 1 to 4.
[1816] For use in the present methods for treating or preventing a
viral infection, a preferred subclass of the compounds of Formula
(XIII) is that wherein, in the compound of Formula (XIII):
[1817] R.sub.1 is --H;
[1818] R.sub.2 is --H or --CH; and
[1819] n is 1 to 4.
[1820] For use in the present methods for treating or preventing a
viral infection, a more preferred subclass of the compounds of
Formula (XIII) is that wherein, in the compound of Formula
(XIII):
[1821] R.sub.1 is --H;
[1822] R.sub.2 is --H or --CH.sub.3; and
[1823] n is 2.
[1824] The invention further provides methods for inhibiting the
replication or infectivity of a virus comprising contacting a virus
or a virus-infected cell with an effective amount of a compound
having the general Formula (XIII) or a pharmaceutically acceptable
salt thereof, wherein, in the compound of Formula (XIII):
[1825] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, or --C(O)OCH.sub.2C.sub.6H.sub.5;
[1826] R.sub.2 is --H or a C.sub.1-C.sub.10 straight chain alkyl;
and
[1827] n is 1 to 4.
[1828] For use in the methods for inhibiting the replication or
infectivity of a virus, a preferred subclass of the compounds of
Formula (XIII) are those wherein:
[1829] R.sub.1 is --H;
[1830] R.sub.2 is --H or --CH.sub.3; and
[1831] n is 1 to 4.
[1832] For use in the methods for inhibiting the replication or
infectivity of a virus, a more preferred subclass of the compounds
of Formula (XIII) are those wherein:
[1833] R.sub.1 is --H;
[1834] R.sub.2 is --H or --CH.sub.3; and
[1835] n is 2.
[1836] The invention further provides methods for causing
immunosuppression in a patient comprising administering to a
patient in need thereof an effective amount of a compound of
Formula (XIII) or a pharmaceutically acceptable salt thereof,
wherein, in the compound of Formula (XIII):
[1837] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, or --C(O)OCH.sub.2C.sub.6H.sub.5;
[1838] R.sub.2 is --H or a C.sub.1-C.sub.10 straight chain alkyl;
and
[1839] n is 1 to 4.
[1840] For use in the methods for causing immunosuppression, a
preferred subclass of the compounds of Formula (XIII) are those
wherein:
[1841] R.sub.1 is --H;
[1842] R.sub.2 is --H or --CH.sub.3; and
[1843] n is 1 to 4.
[1844] For use in the methods for causing immunosuppression, a more
preferred subclass of the compounds of Formula (XIII) are those
wherein:
[1845] R.sub.1 is --H;
[1846] R.sub.2 is --H or --CH.sub.3; and
[1847] n is 2.
[1848] The invention further provides methods for treating or
preventing an autoimmune disease in a patient comprising
administering to a patient in need of such treatment or prevention
an effective amount of a compound of Formula (XIII) or a
pharmaceutically acceptable salt thereof, wherein, in the compound
of Formula (XIII):
[1849] each R.sub.1 is independently selected from the group
consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5,
--C(O)OC(CH.sub.3).sub.3, or --C(O)OCH.sub.2C.sub.6H.sub.5;
[1850] R.sub.2 is --H or a C.sub.1-C.sub.10 straight chain alkyl;
and
[1851] n is 1 to 4.
[1852] For use in the methods for treating or preventing an
autoimmune disease, a preferred subclass of the compounds of
Formula (XIII) are those wherein:
[1853] R.sub.1 is --H;
[1854] R.sub.2 is --H or --CH.sub.3; and
[1855] n is 1 to 4.
[1856] For use in the methods for treating or preventing an
autoimmune disease, a more preferred subclass of the compounds of
Formula (XIII) are those wherein:
[1857] R.sub.1 is --H;
[1858] R.sub.2 is --H or --CH.sub.3; and
[1859] n is 2.
5.14. Racemates and Enantiomers of Formula (I-V) Compounds
[1860] As used herein, the term "Pyrrole-Type compounds" means,
collectively, the compounds of Formulas (I-XIII) and racemates and
enantiomers thereof, and pharmaceutically acceptable salts
thereof.
5.15. Synthesis of the Pyrrole-Type Compounds
[1861] The compounds of the invention can be obtained via
conventional organic syntheses, e.g., as described below. Schemes
A-O indicate methods by which compounds of the invention may be
obtained.
[1862] 5.15.1. The Compounds of Formula (I)
[1863] The compounds of Formula (I) can be obtained using
conventional organic synthesis or by the following illustrative
method shown in Scheme A: 26
[1864] Compound 1 is condensed with compound 2 in the presence of
methanesulfonic acid to produce compound 3. The tosyl group is
removed from compound 3 with 1,3-diaminopropane to provide compound
4 which is treated with POCl.sub.3-DMF to provide aldehyde 5.
Treatment of aldehyde 5 with sodium hydroxide cyclizes the two
pyrrole rings to provide the tetracyclic compound 6 which is
treated with triflic anhydride to provide the triflate 7. Reaction
of the triflate 7 with (1-tert-butoxycarbonylpyr- rol-2-yl)boronic
acid 8 as described in U.S. Pat. No. 5,847,127 provides the
compound of Formula (I).
[1865] Compound 1 can be obtained as shown below in Scheme A.1.
27
[1866] The methods shown in Scheme A.1 for the formation of
compound 1 have been described in A. Furstner et al., J. Am. Chem.
Soc., 1998, 120, 8305-8314.
[1867] (1-tert-butoxycarbonylpyrrol-2-yl)boronic acid 8 is prepared
according to the method in R. D'Alessio et al., Synlett, 1966,
513-514.
[1868] 5.15.2. The Compounds of Formula (II)
[1869] The compounds of Formula (II) can be obtained using
conventional organic synthesis or by the following illustrative
method shown in Scheme B: 28
[1870] Compound 9 is condensed with compound 2 in the presence of
methanesulfonic acid to provide compound 10. The tosyl group is
removed from compound 10 with 1,3-diaminopropane to provide
compound 11 which is treated with POCl.sub.3-DMF to provide
aldehyde 12. Treatment of aldehyde 12 with sodium hydroxide
cyclizes the two pyrrole rings to provide the tetracyclic compound
13 which is treated with triflic anhydride to provide the triflate
14. Reaction of the triflate 14 with
(1-tert-butoxycarbonylpyrrol-2-yl)boronic acid 8 as described in
U.S. Pat. No. 5,847,127 provides the compound of Formula (II).
[1871] Compound 9 can be obtained as shown below in Scheme B.1.
29
[1872] The methods shown in Scheme B.1. for the formation of
compound 9 have been described in A. Furstner et al., J. Am. Chem.
Soc., 1998, 120, 8305-8314.
[1873] (1-tert-butoxycarbonylpyrrol-2-yl)boronic acid 8 is prepared
according to the method in R. D'Alessio et al., Synlett, 1966,
513-514.
[1874] 5.15.3. The Compounds of Formula (III)
[1875] The compounds of Formula (III) can be obtained using
conventional organic synthesis or by the following illustrative
methods shown in Schemes C and D: 30
[1876] Compound 15 is prepared according to the method of D. L.
Boger et al., J. Org. Chem, 1988, 53, 1405-1415 and converted to
the dipyrrole carboxylic ester 16 by treatment with lithium
methoxide in methanol and then to the lithium salt of the dipyrrole
carboxylic acid 17 by treatment with lithium hydroxide in methanol.
The lithium salt of the dipyrrole carboxylic acid 17 is treated
with an alkyl lithium or phenyl lithium (R.sub.3Li) to provide the
dipyrrole ketone 18 which is then coupled with the pyrrole 19
according to the method of D. L Boger et al., J. Org. Chem, 1988,
53, 1405-1415 to provide the compound of Formula (III). 31
[1877] Compound 20 is coupled with pyrrole 21 to provide compound
22 which is treated with triflic anhydride to provide the triflate
23. Pyrrole 21 is prepared by treating pyrrole 24 with POCl.sub.3
and R.sub.3C(O)N(CH.sub.3).sub.2. The triflate 23 is then coupled
with (1-tert-butoxycarbonylpyrrol-2-yl)boronic acid 8 according to
the method in U.S. Pat. No. 5,847,127 to provide the compound of
Formula (III).
[1878] Compound 20 is prepared according to the procedure in L. Duc
et al., Synthesis, 1992, 391-394.
[1879] (1-tert-butoxycarbonylpyrrol-2-yl)boronic acid 8 is prepared
according to the method in R. D'Alessio et al., Synlett, 1966,
513-514.
[1880] 5.15.4. The Compounds of Formula (IV)
[1881] The compounds of Formula (IV) can be obtained using
conventional organic synthesis or by the methods shown in Schemes E
and F: 32
[1882] Compound 15 is prepared according to the method of D. L.
Boger et al., J. Org. Chem, 1988, 53, 1405-1415 and converted to
the dipyrrole carboxylic ester 16 by treatment with lithium
methoxide in methanol and then to the lithium salt of the dipyrrole
carboxylic acid 17 by treatment with lithium hydroxide in methanol.
The lithium salt of the dipyrrole carboxylic acid 17 is then
treated with an alkyl lithium or phenyl lithium (R.sub.3Li) to
provide the dipyrrole ketone 18 which is coupled with pyrrole 25
according to the method of D. L. Boger et al., J. Org. Chem, 1988,
53, 1405-1415 to provide the compound of Formula (IV).
[1883] Pyrrole 25 can be obtained starting with the appropriate
substituted cycloalkanone 26 as shown in Scheme E.1. 33
[1884] The reaction of cycloalkanone 26 with
2,4,6-tri-i-propylphenylsulfo- nyl hydrazine gives the
corresponding hydrazone 27. Compound 27 is reacted with
sec-butyllithium and N,N-dimethylformamide (DMF) to give the
.alpha.,.beta.-unsaturated aldehyde 28. The anion of a
dimethylthioacetaldehyde reagent 29 is generated using
n-butyllithium and adds to the conjugated system of 28 producing
30. The group R.sub.4 in 30 may be hydrogen or a C.sub.1-C.sub.12
alkyl. Reaction of 30 with mercury(II) chloride and calcium
carbonate converts the dimethylthiocarbonyl 30 into a carbonyl
group generating 31. Compound 31 reacts with ammonium carbonate in
DMF providing the pyrrole 25. The methods shown in Scheme E.1 for
the chemical transformation of compound 26 into compound 25 have
been described by H. H. Wasserman and J. M. Fukuyama, Tetrahedron
Lett. 25, 1387-1388, 1984. 34
[1885] Compound 32 is coupled with pyrrole 33 to provide compound
34 which is treated with triflic anhydride to provide the triflate
35. Pyrrole 33 is prepared by treating pyrrole 36 with POCl.sub.3
and R.sub.3C(O)N(CH.sub.3).sub.2. The triflate 35 is then coupled
with (1-tert-butoxycarbonylpyrrol-2-yl)boronic acid 8 according to
the method in U.S. Pat. No. 5,847,127 to provide the compound of
Formula (IV).
[1886] Compound 32 is prepared according to the procedure in L. Duc
et al., Synthesis, 1992, 391-394.
[1887] (1-tert-butoxycarbonylpyrrol-2-yl)boronic acid 8 is prepared
according to the method in R. D'Alessio et al., Synlett, 1966,
513-514. Pyrrole 33 can be obtained starting with the appropriate
substituted cycloalkanone 26 as shown in Scheme E.1.
[1888] 5.15.5. The Compounds of Formula (V)
[1889] The compounds of Formula (V) can be obtained using
conventional organic synthesis or by the methods shown in Schemes G
and H: 35
[1890] Compound 15 is prepared according to the method of D. L.
Boger et al., J. Org. Chem, 1988, 53, 1405-1415 and converted to
the dipyrrole carboxylic ester 16 by treatment with lithium
methoxide in methanol and then to the lithium salt of the dipyrrole
carboxylic acid 17 by treatment with lithium hydroxide in methanol.
The lithium salt of the dipyrrole carboxylic acid 17 is then
treated with methyl lithium or benzyl lithium (R.sub.3Li) to
provide the dipyrrole ketone 18 which is coupled with the pyrrole
37 according to the method of D. L. Boger et al., J. Org. Chem,
1988, 53, 1405-1415 to provide the compound of Formula (V). 36
[1891] In Scheme G.1., R.sub.14 is R.sub.7 less its .alpha.-carbon.
These methods have been described by A. Furstner et al., J. Am.
Chem. Soc. 120, 8305-8314, 1998. Compounds 37 where m is 2-5 are
prepared by replacing cis-cyclooctene (m=1) with cis-cyclononene,
cis-cyclodecene, cis-cycloundecene, and cis-cyclododecene (m=2, 3,
4, and 5, respectively). The structure of the R.sub.7 group (--H, a
C.sub.1-C.sub.10 straight chain alkyl, or --CH(CH.sub.3).sub.2,) in
compounds 37 is determined by the choice of the acid chloride,
R.sub.14C(O)Cl. Acid chlorides are prepared from their
corresponding carboxylic acids by using thionyl chloride, oxalyl
chloride, and/or other methods known in the art. 3738
[1892] Compound 32 is coupled with pyrrole 38 to provide the
compound 39 which is treated with triflic anhydride to provide
triflate 40. Pyrrole 38 is prepared by treating pyrrole 41 with
POCl.sub.3 and R.sub.3C(O)N(CH.sub.3).sub.2. The triflate 40 is
then coupled with (1-tert-butoxycarbonylpyrrol-2-yl)boronic acid 8
according to the method in U.S. Pat. No. 5,847,127 to provide the
compound of Formula (V).
[1893] Compound 32 is prepared according to the procedure in L. Duc
et al., Synthesis, 1992, 391-394.
[1894] (1-tert-butoxycarbonylpyrrol-2-yl)boronic acid 8 is prepared
according to the method in R. D'Alessio et al., Synlett, 1966,
513-514.
[1895] 5.15.6. The Compounds of Formula (VI, VII, and VIII)
[1896] The compounds of Formula (VI), (VII), and (VIII) can be
obtained using conventional organic synthesis or by the methods
shown in Scheme I.1.: 39
[1897] Compound 42 is condensed with pyrrole 37 to provide the
compound of Formula (VI), with pyrrole 43 to provide the compound
of Formula (VII), or pyrrole 25 to provide the compound of Formula
(VIII).
[1898] Compound 42 is obtained by the procedure described in A. J.
Blake et al., J. Chem. Soc., Chem. Comm., 1990, 734-736.
[1899] Pyrrole 37 is obtained as shown in Scheme G.1. In Scheme
G.1., R.sub.14 is R.sub.3 less its .alpha.-carbon. The methods of
Scheme G.1. for the formation of compound 37 have been described in
A. Furstner et al., J. Am. Chem. Soc., 1998, 120, 8305-8314.
[1900] Pyrrole 25 can be obtained starting with the appropriate
substituted cycloalkanone 26 as shown in Scheme E.1. The methods
shown in Scheme E.1 for the chemical transformation of compound 26
into compound 25 have been described by H. H. Wasserman and J. M.
Fukuyama, Tetr. Lett. 25, 1387-1388, 1984.
[1901] Pyrroles 43 are commercially available or can be readily
prepared from commercially available starting materials using
methods well known to those of ordinary skill in the art (See,
e.g., G. P. Bear, "The Synthesis of 1-H-Pyrroles" in "Pyrroles,"
vol. 1, edited by R. A. Jones, Wiley, NY, 1990, 105-294.; J. H. Liu
et al., J. Org. Chem., 2000, 65, 3274-3283; D. Enders et al., Tetr.
Lett., 1995, 35, 8007-8010; and J. Tang and J. G. Verkade, J. Org.
Chem., 1994, 59, 7793-7802; and B. Franck et al., Liebigs Ann.
Chemie, 1994, 503-510).
[1902] 5.15.6.1 The Compounds of Formula (VII)
[1903] In one embodiment, the compounds of Formula (VII), wherein
R.sub.2 and R.sub.4 are defined above for the compounds of Formula
(VII), can be obtained using conventional organic synthesis or by
the methods shown in Scheme I.2. below: 40
[1904] The aldehydic pyrrole 81 and the heterocyclic boronate 86
are prepared as shown in Scheme I.2. Compound 81 is then coupled
with synthetically or commercially accessible 82 to give Compound
83, which is then converted to the triflate 84. A compound of
Formula (VII) is obtained from Suzuki coupling of the boronate 86
and the triflate 84.
[1905] 5.15.7. The Compounds of Formula (IX)
[1906] The compounds of Formula (IX) can be obtained using
conventional organic synthesis or by the methods shown in Scheme J:
41
[1907] Pyrrole 37 is converted to aldehyde 45 with POCl.sub.3 in
DMF and then to compound 46 by treatment with potassium hydride and
SEMCl. Compound 46 is reacted with compound 47, prepared using the
method described in A. Furstner et al., J. Amer. Chem. Soc., 1998,
120, 2817-2825, to provide compound 48. The tri-isopropylsilyl
group is removed from compound 48 using tetra-butylammonium
fluoride (TBAF) in tetrahydrofuran to provide the compound of
Formula (IX).
[1908] Pyrrole 44 can be obtained using the method shown in Scheme
G.1. The methods of Scheme G.1. for the formation of compound 37
have been described in A. Furstner et al., J. Am. Chem. Soc., 1998,
120, 8305-8314.
[1909] 5.15.8. The Compounds of Formula (X)
[1910] The compounds of Formula (X) can be obtained using
conventional organic synthesis or by the methods shown in Scheme K:
42
[1911] Dipyrrole aldehyde 49 is condensed with compound 50 using
POCl.sub.3 or H.sup.+ in an organic solvent, such as methanol, to
provide the compound of Formula (X).
[1912] Dipyrrole aldehyde 49 can be prepared by the method of D. L.
Boger et al., J. Org. Chem, 1988, 53, 1405-1415. Compound 50 can be
prepared from commercially available starting materials using
methods well known to those of ordinary skill in the art (See,
e.g., B. Robinson, "The Fischer Indole Synthesis," Wiley, NY, 1983;
H. Ishii, Accts. Chem. Res., 1981, 14, 275-283; and D. C. Soderberg
et al., J. Org. Chem., 1999, 64, 9731-9734).
[1913] Representative examples of the synthesis of compounds of
Formula (X) are provided in Scheme K.1. and K.2. below: 43 44
[1914] 5.15.9. The Compounds of Formula (XI)
[1915] The compounds of Formula (XI) can be obtained using
conventional organic synthesis or by the methods shown in Scheme L:
45
[1916] Dipyrrole aldehyde 49 is condensed with compound 51 using
POCl.sub.3 or H.sup.+ to provide the compound of Formula (XI).
[1917] Dipyrrole aldehyde 49 can be prepared by the method of D. L.
Boger et al., J. Org. Chem, 1988, 53, 1405-1415. Compound 51 can be
prepared from commercially available starting materials using
methods well known to those of ordinary skill in the art (See,
e.g., B. Robinson, "The Fischer Indole Synthesis," Wiley, NY, 1983;
H. Ishii, Accts. Chem. Res., 1981, 14, 275-283; D. C. Soderberg et
al., J. Org. Chem., 1999, 64, 9731-9734, Anderson and Loader,
Synthesis, 1985, 353-364; and E. Abel et al., Chem. Comm., 2000,
433-434).
[1918] Specific examples of the synthesis of compounds of Formula
(XI) are provided in Scheme L.1., L.2, and L.3. below: 46 47 48
[1919] 5.15.10. The Compounds of Formula (XII)
[1920] The compounds of Formula (XII) can be obtained using
conventional organic synthesis or, except for R.sub.3=to --H,
--SO.sub.2CH.sub.3, and --SO.sub.2C.sub.6H.sub.5, by the methods
shown in Scheme M: 49
[1921] Dipyrrole aldehyde 49 is condensed with compound 52 using
POCl.sub.3 or H.sup.+ to provide compound 53. Compound 53 is then
treated with methanesulfonyl chloride to provide the mesylate 54
which is hydrogenated over palladium and charcoal, treated with
iodotrimethylsilane, or treated with boron tribromide to remove the
benzyl group and provide compound 55. Treatment of compound 55 with
triethylamine provides the compound of Formula (XII).
Alternatively, the benzyl group can be removed from compound 53 by
hydrogenolysis to provide compound 56 which can be treated with
triphenylphosphine and DEAD to provide the compound of Formula
(XII).
[1922] Dipyrrole aldehyde 49 can be prepared by the method of D. L.
Boger et al., J. Org. Chem, 1988, 53, 1405-1415. Compound 52 can be
prepared by the method of M. A. Warpehoski et al., J. Med. Chem.,
1988, 31, 590-603.
[1923] Compounds of Formula (XII), wherein R.sub.3 is --H are
prepared by the following reaction: 50
[1924] Compounds of Formula (XII), wherein R.sub.3 is
--SO.sub.2CH.sub.3 or --SO.sub.2C.sub.6H.sub.5 can be prepared by
the methods shown in Scheme N: 51
[1925] Compound 57 is condensed with compound 49, prepared by the
method of D. L. Boger et al., J. Org. Chem, 1988, 53, 1405-1415, to
provide compound 58. Compound 58 is treated with methanesulfonyl
chloride; hydrogenated over palladium and charcoal, reacted with
trimethylsilane, or reacted with tribromoborane; and treated with
triethylamine to provide a compound of Formula (XII), wherein
R.sub.3 is --SO.sub.2CH.sub.3 or --SO.sub.2C.sub.6H.sub.5.
[1926] Compound 57 can be prepared by the method of M. A.
Warpehoski et al., J. Med. Chem., 1988, 31, 590-603.
[1927] 5.15.11. The Compounds of Formula (XIII)
[1928] The compounds of Formula (XIII) can be obtained using
conventional organic synthesis or by the methods shown in Scheme O:
525354
[1929] Compound 59 is treated with tert-butyldimethylsilyl chloride
in the presence of imidazole to provide compound 60 which is then
treated with ArSO.sub.2NHNH.sub.2 to provide compound 61. Treatment
of compound 61 with sec-butyl lithium provides the unsaturated
aldehyde 62 which is reacted with (MeS).sub.2CHR.sub.2 in the
presence of n-butyl lithium to provide compound 63 which is
converted with mercury (II) chloride to the dicarbonyl compound 64.
Dicarbonyl compound 64 is then treated with ammonium carbonate to
provide compound 65. Reaction of compound 65 with (BOC).sub.2O
followed by treatment with aqueous acetic acid provides compound
66. Compound 66 is reacted with commercially available pyrrolinone
67, in the presence of n-butyl lithium to provide compound 68. The
BOC group is removed from compound 68 to provide compound 69 which
is treated with POCl.sub.3-DMF to provide aldehyde 70. Aldehyde 70
is then reacted with sodium hydroxide in DMSO to provide compound
71 which is reacted with triflic anhydride to provide triflate 72.
Triflate 72 is reacted with
(1-tert-butoxycarbonylpyrrol-2-yl)boronic acid 8, prepared
according to the method in R. D'Alessio et al., Synlett, 1966,
513-514, to provide the compound of Formula (XIII).
[1930] Alternatively, compound 71 can be prepared by treating
compound 65 with POCl.sub.3-DMF followed by an alkaline quench to
provide compound 73 which is reacted with pyrrolinone 67 in the
presence of sodium hydroxide in DMSO to provide compound 74 which
is treated with aqueous sodium acetate to provide compound 75.
Compound 75 is treated with trimethylsulfonic acid to provide
compound 71.
[1931] Once the compounds of Formula (I)-(XIII) have been
synthesized, they can be purified or substantially purified, using
conventional chromatography, recrystallization or other
purification techniques known to those skilled in the art.
[1932] 5.15.12. Illustrative Pyrrole-Type Compounds
[1933] Illustrative compounds of Formula (III) are: 55
[1934]
5'-[1-(3,5-Dimethyl-1H-pyrrol-2-yl)-ethylidene]-4'-methoxy-1H,5'H-[-
2,2']bipyrrolyl; 56
[1935]
4'-Methoxy-5'-[1-(1H-pyrrol-2-yl)-ethylidene]-1H,5'H-[2,2']bipyrrol-
yl;
[1936] and pharmaceutically acceptable salts thereof.
[1937] Illustrative compounds of Formula (IV) are: 57
[1938]
4'-Methoxy-5'-[1-(2,4,5,6-tetrahydro-cyclopenta[c]pyrrol-1-yl)-ethy-
lidene]-1H, 5'H-[2,2']bipyrrolyl; 58
[1939]
1-[1-(4-Methoxy-1'H-[2,2']bipyrrolyl-5-ylidene)-ethyl]-4,5,6,7-tetr-
ahydro-2H-isoindole;
[1940] and pharmaceutically acceptable salts thereof.
[1941] An illustrative compound of Formula (VII) is: 59
[1942]
2-(4-Methoxy-[2,2']bithiophenyl-5-ylmethylene]-2H-pyrrole;
[1943] and pharmaceutically acceptable salts thereof.
[1944] Illustrative compounds of Formula (VIII) are: 60
[1945]
1-(4-Methoxy-[2,2']bithiophenyl-5-ylmethylene)-4,5,6,7-tetrahydro-1-
H-isoindole; 61
[1946]
1-(4-Methoxy-[2,2']bithiophenyl-5-ylmethylene)-1,4,5,6-tetrahydro-c-
yclopenta[c]pyrrole;
[1947] and pharmaceutically acceptable salts thereof.
[1948] An illustrative compound of Formula (XI) is: 62
[1949]
2-(4-Methoxy-1'H-[2,2']bipyrrolyl-5-ylidenemethyl)-1H-indole;
[1950] and pharmaceutically acceptable salts thereof.
5.16. Therapeutic/Prophylactic Administration and Compositions
[1951] As used herein, the novel compounds of the present
invention, the compounds of the present compositions, the compounds
of the present methods, and pharmaceutically acceptable salts of
these compounds are referred to collectively herein as
"Pyrrole-Type compounds".
[1952] Due to the activity of the Pyrrole-Type compounds, the
Pyrrole-Type compounds are advantageously useful in veterinary and
human medicine. For example, the Pyrrole-Type compounds are useful
for the treatment or prevention of cancer or neoplastic disease or
inhibiting the growth of a cancer cell or neoplastic cell. The
Pyrrole-Type compounds are also useful for the treatment or
prevention of a viral infection or inhibiting the replication or
infectivity of a virus. The Pyrrole-Type compounds are also useful
for causing immunosuppression. The Pyrrole-Type compounds are also
useful for treating or preventing an autoimmune disease.
[1953] When administered to a subject, e.g., an animal for
veterinary use or to a human for clinical use, or when made to
contact a cell or tissue, the Pyrrole-Type compounds are preferably
in isolated form. By "isolated" it is meant that prior to
administration or contacting, a Pyrrole-Type compound is separated
from other components of a synthetic organic chemical reaction
mixture or natural product source, e.g., plant matter, tissue
culture, bacterial broth, etc. Preferably, the Pyrrole-Type
compounds are isolated via conventional techniques, e.g.,
extraction followed by chromatography, recrystalization, or another
conventional technique. When in isolated form, the Pyrrole-Type
compounds are at least 90%, preferably at least 95%, of a single
Pyrrole-Type compound by weight of that which is isolated. "Single
Pyrrole-Type compound" means an enantiomer or a racemate of a
Pyrrole-Type compound.
[1954] The invention provides methods of treatment and prophylaxis
by administration to a subject of an effective amount of a
Pyrrole-Type compound. The subject is preferably an animal,
including, but not limited, to an animal such a cow, horse, sheep,
pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, guinea
pig, etc., and is more preferably a mammal, and most preferably a
human.
[1955] The present compositions, which comprise one or more
Pyrrole-Type compounds, may be administered by any convenient
route, for example by infusion or bolus injection, by absorption
through epithelial or mucocutaneous linings (e.g., oral mucosa,
rectal and intestinal mucosa, etc.) and may be administered
together with another biologically active agent. Administration can
be systemic or local. Various delivery systems are known, e.g.,
encapsulation in liposomes, microparticles, microcapsules,
capsules, etc., and can be used to administer a Pyrrole-Type
compound of the invention. In certain embodiments, more than one
Pyrrole-Type compound of the invention is administered to a
subject. Methods of administration include but are not limited to
intradermal, intramuscular, intraperitoneal, intravenous,
subcutaneous, intranasal, epidural, oral, sublingual, intranasal,
intracerebral, intravaginal, transdermal, rectally, by inhalation,
or topically to the ears, nose, eyes, or skin. The preferred mode
of administration is left to the discretion of the practitioner,
and will depend in-part upon the site of the medical condition
(such as the site of cancer or viral infection).
[1956] In specific embodiments, it may be desirable to administer
one or more Pyrrole-Type compounds of the invention locally to the
area in need of treatment. This may be achieved, for example, and
not by way of limitation, by local infusion during surgery, topical
application, e.g., in conjunction with a wound dressing after
surgery, by injection, by means of a catheter, by means of a
suppository, or by means of an implant, said implant being of a
porous, non-porous, or gelatinous material, including membranes,
such as sialastic membranes, or fibers. In one embodiment,
administration can be by direct injection at the site (or former
site) of a cancer, tumor or neoplastic or pre-neoplastic tissue. In
another embodiment, administration can be by direct injection at
the site (or former site) of a viral infection, tissue or organ
transplant, or autoimmune response.
[1957] In certain embodiments, it may be desirable to introduce one
or more Pyrrole-Type compounds of the invention into the central
nervous system by any suitable route, including intraventricular
and intrathecal injection. Intraventricular injection may be
facilitated by an intraventricular catheter, for example, attached
to a reservoir, such as an Ommaya reservoir.
[1958] Pulmonary administration can also be employed, e.g., by use
of an inhaler or nebulizer, and formulation with an aerosolizing
agent, or via perfusion in a fluorocarbon or synthetic pulmonary
surfactant. In certain embodiments, the Pyrrole-Type compounds can
be formulated as a suppository, with traditional binders and
carriers such as triglycerides.
[1959] In another embodiment, the Pyrrole-Type compounds of the
invention can be delivered in a vesicle, in particular a liposome
(see Langer, Science 249:1527-1533 (1990); Treat et al., in
Liposomes in the Therapy of Infectious Disease and Cancer,
Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365
(1989); Lopez-Berestein, ibid., pp. 317-327; see generally
ibid.)
[1960] In yet another embodiment, the Pyrrole-Type compounds can be
delivered in a controlled release system. In one embodiment, a pump
may be used (see Langer, supra; Sefton. CRC Crit. Ref. Biomed. Eng.
14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et
al., N. Engl. J. Med. 321:574 (1989)). In another embodiment,
polymeric materials can be used (see Medical Applications of
Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton,
Fla. (1974); Controlled Drug Bioavailability, Drug Product Design
and Performance, Smolen and Ball (eds.), Wiley, New York (1984);
Ranger and Peppas, J. Macromol. Sci. Rev. Macromol. Chem. 23:61
(1983); see also Levy et al., Science 228:190 (1985); During et
al., Ann. Neurol. 25:351 (1989); Howard et al., J. Neurosurg.
71:105 (1989)). In yet another embodiment, a controlled-release
system can be placed in proximity of the target of the Pyrrole-Type
compounds, e.g., the brain, thus requiring only a fraction of the
systemic dose (see, e.g., Goodson, in Medical Applications of
Controlled Release, supra, vol. 2, pp. 115-138 (1984)). Other
controlled-release systems discussed in the review by Langer
(Science 249:1527-1533 (1990)) may be used.
[1961] The present compositions will contain an effective amount of
a Pyrrole-Type compound, preferably in purified form, together with
a suitable amount of a pharmaceutically acceptable carrier so as to
provide the form for proper administration to the patient.
[1962] In a specific embodiment, the term "pharmaceutically
acceptable" means approved by a regulatory agency of the Federal or
a state government or listed in the U.S. Pharmacopeia or other
generally recognized pharmacopeia for use in animals, and more
particularly in humans. The term "carrier" refers to a diluent,
adjuvant, excipient, or vehicle with which a Pyrrole-Type compound
is administered. Such pharmaceutical carriers can be liquids, such
as water and oils, including those of petroleum, animal, vegetable
or synthetic origin, such as peanut oil, soybean oil, mineral oil,
sesame oil and the like. The pharmaceutical carriers can be saline,
gum acacia, gelatin, starch paste, talc, keratin, colloidal silica,
urea, and the like. In addition, auxiliary, stabilizing,
thickening, lubricating and coloring agents may be used. When
administered to a subject, the Pyrrole-Type compounds and
pharmaceutically acceptable carriers are preferably sterile. Water
is a preferred carrier when the Pyrrole-Type compound is
administered intravenously. Saline solutions and aqueous dextrose
and glycerol solutions can also be employed as liquid carriers,
particularly for injectable solutions. Suitable pharmaceutical
carriers also include excipients such as starch, glucose, lactose,
sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium
stearate, glycerol monostearate, talc, sodium chloride, dried skim
milk, glycerol, propylene, glycol, water, ethanol and the like. The
present compositions, if desired, can also contain minor amounts of
wetting or emulsifying agents, or pH buffering agents.
[1963] The present compositions can take the form of solutions,
suspensions, emulsion, tablets, pills, pellets, capsules, capsules
containing liquids, powders, sustained-release formulations,
suppositories, emulsions, aerosols, sprays, suspensions, or any
other form suitable for use. In one embodiment, the
pharmaceutically acceptable carrier is a capsule (see e.g., U.S.
Pat. No. 5,698,155). Other examples of suitable pharmaceutical
carriers are described in "Remington's Pharmaceutical Sciences" by
E. W. Martin.
[1964] The phrase "pharmaceutically acceptable salt(s)," as used
herein includes but are not limited to salts of acidic or basic
groups that may be present in compounds used in the present
compositions. Compounds included in the present compositions that
are basic in nature are capable of forming a wide variety of salts
with various inorganic and organic acids. The acids that may be
used to prepare pharmaceutically acceptable acid addition salts of
such basic compounds are those that form non-toxic acid addition
salts, i.e., salts containing pharmacologically acceptable anions,
including but not limited to sulfuric, citric, maleic, acetic,
oxalic, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate,
bisulfate, phosphate, acid phosphate, isonicotinate, acetate,
lactate, salicylate, citrate, acid citrate, tartrate, oleate,
tannate, pantothenate, bitartrate, ascorbate, succinate, maleate,
gentisinate, fumarate, gluconate, glucaronate, saccharate, formate,
benzoate, glutamate, methanesulfonate, ethanesulfonate,
benzenesulfonate, p-toluenesulfonate and pamoate (i.e.,
1,1'-methylene-bis-(2-hydroxy-3-nap- hthoate)) salts. Compounds
included in the present compositions that include an amino moiety
may form pharmaceutically or cosmetically acceptable salts with
various amino acids, in addition to the acids mentioned above.
Compounds, included in the present compositions, that are acidic in
nature are capable of forming base salts with various
pharmacologically or cosmetically acceptable cations. Examples of
such salts include alkali metal or alkaline earth metal salts and,
particularly, calcium, magnesium, sodium lithium, zinc, potassium,
and iron salts.
[1965] In a preferred embodiment, the Pyrrole-Type compounds are
formulated in accordance with routine procedures as a
pharmaceutical composition adapted for intravenous administration
to human beings. Typically, Pyrrole-Type compounds for intravenous
administration are solutions in sterile isotonic aqueous buffer.
Where necessary, the compositions may also include a solubilizing
agent. Compositions for intravenous administration may optionally
include a local anesthetic such as lignocaine to ease pain at the
site of the injection. Generally, the ingredients are supplied
either separately or mixed together in unit dosage form, for
example, as a dry lyophilized powder or water free concentrate in a
hermetically sealed container such as an ampoule or sachette
indicating the quantity of active agent. Where the Pyrrole-Type
compound is to be administered by infusion, it can be dispensed,
for example, with an infusion bottle containing sterile
pharmaceutical grade water or saline. Where the Pyrrole-Type
compound is administered by injection, an ampoule of sterile water
for injection or saline can be provided so that the ingredients may
be mixed prior to administration.
[1966] Compositions for oral delivery may be in the form of
tablets, lozenges, aqueous or oily suspensions, granules, powders,
emulsions, capsules, syrups, or elixirs, for example. Orally
administered compositions may contain one or more optionally
agents, for example, sweetening agents such as fructose, aspartame
or saccharin; flavoring agents such as peppermint, oil of
wintergreen, or cherry; coloring agents; and preserving agents, to
provide a pharmaceutically palatable preparation. Moreover, where
in tablet or pill form, the compositions may be coated to delay
disintegration and absorption in the gastrointestinal tract thereby
providing a sustained action over an extended period of time.
Selectively permeable membranes surrounding an osmotically active
driving compound are also suitable for orally administered
Pyrrole-Type compounds. In these later platforms, fluid from the
environment surrounding the capsule is imbibed by the driving
compound, which swells to displace the agent or agent composition
through an aperture. These delivery platforms can provide an
essentially zero order delivery profile as opposed to the spiked
profiles of immediate release formulations. A time delay material
such as glycerol monostearate or glycerol stearate may also be
used. Oral compositions can include standard carriers such as
mannitol, lactose, starch, magnesium stearate, sodium saccharine,
cellulose, magnesium carbonate, etc. Such carriers are preferably
of pharmaceutical grade.
[1967] The amount of the Pyrrole-Type compound that will be
effective in the treatment of a particular disorder or condition
will depend on the nature of the disorder or condition, and can be
determined by standard clinical techniques. In addition, in vitro
or in vivo assays may optionally be employed to help identify
optimal dosage ranges. The precise dose to be employed in the
compositions will also depend on the route of administration, and
the seriousness of the disease or disorder, and should be decided
according to the judgment of the practitioner and each patient's
circumstances. However, suitable dosage ranges for intravenous
administration are generally about 10 micrograms-1 milligram,
preferably about 20-500 micrograms of Pyrrole-Type compound per
kilogram body weight. In specific preferred embodiments of the
invention, the i.v. dose is 10-40, 30-60, 60-100, or 100-200
micrograms per kilogram body weight. In other embodiments, the i.v.
dose is 75-150, 150-250, 250-375 or 375-500 micrograms per kilogram
body weight. Suitable dosage ranges for intranasal administration
are generally about 0.01 pg/kg body weight to 1 mg/kg body weight.
Suppositories generally contain active ingredient in the range of
0.5% to 10% by weight. Oral compositions preferably contain 10% to
95% active ingredient. In specific preferred embodiments of the
invention, suitable dose ranges for oral administration are
generally about 0.1 micrograms-10 milligrams, preferably about 0.75
micrograms-1 milligram, and more preferably about 1-500 micrograms
of active compound per kilogram body weight. In specific preferred
embodiments, the oral dose is 1-10, 10-30, 30-90, or 90-150
micrograms per kilogram body weight. In other embodiments, the oral
dose is 150-250, 250-325, 325-450 or 450-1000 micrograms per
kilogram body weight. Effective doses may be extrapolated from
dose-response curves derived from in vitro or animal model test
systems. Such animal models and systems are well known in the
art.
[1968] The invention also provides pharmaceutical packs or kits
comprising one or more containers filled with one or more
Pyrrole-Type compounds of the invention. Optionally associated with
such container(s) can be a notice in the form prescribed by a
governmental agency regulating the manufacture, use or sale of
pharmaceuticals or biological products, which notice reflects
approval by the agency of manufacture, use or sale for human
administration. In certain preferred embodiment, e.g., when
administered for the treatment or prevention of cancer, the kit may
also contain one or more chemotherapeutic agents useful for
treating cancer or a neoplastic disease to be administered in
combination with a Pyrrole-Type compound of the invention. In
certain preferred embodiments, e.g., when administered for the
treatment or prevention of viral or autoimmune disease, the kit may
contain one or more Pyrrole-Type compound(s) of the invention and
one or more anti-viral or immunosuppressant agents.
[1969] The Pyrrole-Type compounds of the invention are preferably
assayed in vitro, and then in vivo, for the desired therapeutic or
prophylactic activity, prior to use in humans. For example, in
vitro assays can be used to determine whether administration of a
specific Pyrrole-Type compound or combination of Pyrrole-Type
compounds is preferred.
[1970] In one embodiment, a patient tissue sample is grown in
culture, and contacted or otherwise administered with a
Pyrrole-Type compound, and the effect of such Pyrrole-Type compound
upon the tissue sample is observed and compared to a non-contacted
tissue. In other embodiments, a cell culture model is used in which
the cells of the cell culture are contacted or otherwise
administered with a Pyrrole-Type compound, and the effect of such
Pyrrole-Type compound upon the tissue sample is observed and
compared to a non-contacted cell culture. Generally, a lower level
of proliferation or survival of the contacted cells compared to the
non-contracted cells indicates that the Pyrrole-Type compound is
effective to treat a the patient. Such Pyrrole-Type compounds may
also be demonstrated effective and safe using animal model
systems.
[1971] Other methods will be known to the skilled artisan and are
within the scope of the invention.
5.17. Inhibition of Cancer and Neoplastic Cells and Disease
[1972] The Pyrrole-Type compounds may be demonstrated to inhibit
tumor cell proliferation, cell transformation and tumorigenesis in
vitro and in vivo using a variety of assays known in the art, or
described herein. Such assays may use cells of a cancer cell line,
or cells from a patient. Many assays well-known in the art can be
used to assess such survival and/or growth; for example, cell
proliferation can be assayed by measuring (.sup.3H)-thymidine
incorporation, by direct cell count, by detecting changes in
transcription, translation or activity of known genes such as
proto-oncogenes (e.g., fos, myc) or cell cycle markers (Rb, cdc2,
cyclin A, D1, D2, D3, E, etc). The levels of such protein and MRNA
and activity can be determined by any method well known in the art.
For example, protein can be quantitated by known immunodiagnostic
methods such as Western blotting or immunoprecipitation using
commercially available antibodies (for example, many cell cycle
marker antibodies are from Santa Cruz Inc.). mRNA can be
quantitated by methods that are well known and routine in the art,
for example by northern analysis, RNase protection, the polymerase
chain reaction in connection with the reverse transcription, etc.
Cell viability can be assessed by using trypan-blue staining or
other cell death or viability markers known in the art.
Differentiation can be assessed visually based on changes in
morphology, etc.
[1973] The present invention provides for cell cycle and cell
proliferation analysis by a variety of techniques known in the art,
including but not limited to the following:
[1974] As one example, bromodeoxyuridine (BRDU) incorporation may
be used as an assay to identify proliferating cells. The BRDU assay
identifies a cell population undergoing DNA synthesis by
incorporation of BRDU into newly synthesized DNA. Newly synthesized
DNA may then be detected using an anti-BRDU antibody (see Hoshino
et al., 1986, Int. J. Cancer 38, 369; Campana et al., 1988, J.
Immunol. Meth. 107, 79).
[1975] Cell proliferation may also be examined using
(.sup.3H)-thymidine incorporation (see e.g., Chen, J., 1996,
Oncogene 13:1395-403; Jeoung, J., 1995, J. Biol. Chem.
270:18367-73). This assay allows for quantitative characterization
of S-phase DNA synthesis. In this assay, cells synthesizing DNA
will incorporate (.sup.3H)-thymidine into newly synthesized DNA.
Incorporation may then be measured by standard techniques in the
art such as by counting of radioisotope in a Scintillation counter
(e.g. Beckman LS 3800 Liquid Scintillation Counter).
[1976] Detection of proliferating cell nuclear antigen (PCNA) may
also be used to measure cell proliferation. PCNA is a 36 kilodalton
protein whose expression is elevated in proliferating cells,
particularly in early G1 and S phases of the cell cycle and
therefore may serve as a marker for proliferating cells. Positive
cells are identified by immunostaining using an anti-PCNA antibody
(see Li et al., 1996, Curr. Biol. 6:189-199; Vassilev et al., 1995,
J. Cell Sci. 108:1205-15).
[1977] Cell proliferation may be measured by counting samples of a
cell population over time (e.g daily cell counts). Cells may be
counted using a hemacytometer and light microscopy (e.g. HyLite
hemacytometer, Hausser Scientific). Cell number may be plotted
against time in order to obtain a growth curve for the population
of interest. In a preferred embodiment, cells counted by this
method are first mixed with the dye Trypan-blue (Sigma), such that
living cells exclude the dye, and are counted as viable members of
the population.
[1978] DNA content and/or mitotic index of the cells may be
measured, for example, based on the DNA ploidy value of the cell.
For example, cells in the GI phase of the cell cycle generally
contain a 2N DNA ploidy value. Cells in which DNA has been
replicated but have not progressed through mitosis (e.g. cells in
S-phase) will exhibit a ploidy value higher than 2N and up to 4N
DNA content. Ploidy value and cell-cycle kinetics may be further
measured using propidum iodide assay (see e.g. Turner, T., et al.,
1998, Prostate 34:175-81). Alternatively, the DNA ploidy may be
determined by quantitation of DNA Feulgen staining (which binds to
DNA in a stoichiometric manner) on a computerized
microdensitometrystaining system (see e.g., Bacus, S., 1989, Am. J.
Pathol.135:783-92). In an another embodiment, DNA content may be
analyzed by preparation of a chromosomal spread (Zabalou, S., 1994,
Hereditas.120:127-40; Pardue, 1994, Meth. Cell Biol.
44:333-351).
[1979] The expression of cell-cycle proteins (e.g., CycA. CycB,
CycE, CycD, cdc2, Cdk4/6, Rb, p21, p27, etc.) provide crucial
information relating to the proliferative state of a cell or
population of cells. For example, identification in an
anti-proliferation signaling pathway may be indicated by the
induction of p21.sup.cip1. Increased levels of p21 expression in
cells results in delayed entry into G1 of the cell cycle (Harper et
al., 1993, Cell 75:805-816; Li et al., 1996, Curr. Biol.
6:189-199). p21 induction may be identified by immunostaining using
a specific anti-p21 antibody available commercially (e.g. Santa
Cruz). Similarly, cell-cycle proteins may be examined by Western
blot analysis using commercially available antibodies. In another
embodiment, cell populations are synchronized prior to detection of
a cell cycle protein. Cell cycle proteins may also be detected by
FACS (fluorescence-activated cell sorter) analysis using antibodies
against the protein of interest.
[1980] Detection of changes in length of the cell cycle or speed of
cell cycle may also be used to measure inhibition of cell
proliferation by the Pyrrole-Type compounds of the invention. In
one embodiment the length of the cell cycle is determined by the
doubling time of a population of cells (e.g., using cells contacted
or not contacted with one or more Pyrrole-Type compounds of the
invention). In another embodiment, FACS analysis is used to analyze
the phase of cell cycle progression, or purify G1, S, and G2/M
fractions (see e.g., Delia, D. et al., 1997, Oncogene
14:2137-47).
[1981] Lapse of cell cycle checkpoint(s), and/or induction of cell
cycle checkpoint(s), may be examined by the methods described
herein, or by any method known in the art. Without limitation, a
cell cycle checkpoint is a mechanism which ensures that a certain
cellular events occur in a particular order. Checkpoint genes are
defined by mutations that allow late events to occur without prior
completion of an early event (Weinert, T., and Hartwell, L., 1993,
Genetics, 134:63-80). Induction or inhibition of cell cycle
checkpoint genes may be assayed, for example, by Western blot
analysis, or by immunostaining, etc. Lapse of cell cycle
checkpoints may be further assessed by the progression of a cell
through the checkpoint without prior occurrence of specific events
(e.g. progression into mitosis without complete replication of the
genomic DNA).
[1982] In addition to the effects of expression of a particular
cell cycle protein, activity and post-translational modifications
of proteins involved in the cell cycle can play an integral role in
the regulation and proliferative state of a cell. The invention
provides for assays involved in detecting post-translational
modifications (e.g. phosphorylation) by any method known in the
art. For example, antibodies that detect phosphorylated tyrosine
residues are commercially available, and may be used in Western
blot analysis to detect proteins with such modifications. In
another example, modifications such as myristylation, may be
detected on thin layer chromatography or reverse phase h.p.l.c.
(see e.g., Glover, C., 1988, Biochem. J. 250:485-91; Paige, L.,
1988, Biochem J.; 250:485-91).
[1983] Activity of signaling and cell cycle proteins and/or protein
complexes is often mediated by a kinase activity. The present
invention provides for analysis of kinase activity by assays such
as the histone H1 assay (see e.g., Delia, D. et al., 1997, Oncogene
14:2137-47).
[1984] The Pyrrole-Type compounds can also be demonstrated to alter
cell proliferation in cultured cells in vitro using methods which
are well known in the art. Specific examples of cell culture models
include, but are not limited to, for lung cancer, primary rat lung
tumor cells (Swafford et al., 1997, Mol. Cell. Biol., 17:1366-1374)
and large-cell undifferentiated cancer cell lines (Mabry et al.,
1991, Cancer Cells, 3:53-58); colorectal cell lines for colon
cancer (Park and Gazdar, 1996, J. Cell Biochem. Suppl. 24:131-141);
multiple established cell lines for breast cancer (Hambly et al.,
1997, Breast Cancer Res. Treat. 43:247-258; Gierthy et al., 1997,
Chemosphere 34:1495-1505; Prasad and Church, 1997, Biochem.
Biophys. Res. Commun. 232:14-19); a number of well-characterized
cell models for prostate cancer (Webber et al., 1996, Prostate,
Part 1, 29:386-394; Part 2, 30:58-64; and Part 3, 30:136-142;
Boulikas, 1997, Anticancer Res. 17:1471-1505); for genitourinary
cancers, continuous human bladder cancer cell lines (Ribeiro et
al., 1997, Int. J. Radiat. Biol. 72:11-20); organ cultures of
transitional cell carcinomas (Booth et al., 1997, Lab Invest.
76:843-857) and rat progression models (Vet et al., 1997, Biochim.
Biophys Acta 1360:39-44); and established cell lines for leukemias
and lymphomas (Drexler, 1994, Leuk. Res. 18:919-927, Tohyama, 1997,
Int. J. Hematol. 65:309-317).
[1985] The Pyrrole-Type compounds can also be demonstrated to
inhibit cell transformation (or progression to malignant phenotype)
in vitro. In this embodiment, cells with a transformed cell
phenotype are contacted with one or more Pyrrole-Type compounds,
and examined for change in characteristics associated with a
transformed phenotype (a set of in vitro characteristics associated
with a tumorigenic ability in vivo), for example, but not limited
to, colony formation in soft agar, a more rounded cell morphology,
looser substratum attachment, loss of contact inhibition, loss of
anchorage dependence, release of proteases such as plasminogen
activator, increased sugar transport, decreased serum requirement,
or expression of fetal antigens, etc. (see Luria et al., 1978,
General Virology, 3d Ed., John Wiley & Sons, New York, pp.
436-446).
[1986] Loss of invasiveness or decreased adhesion may also be used
to demonstrate the anti-cancer effects of the Pyrrole-Type
compounds. For example, a critical aspect of the formation of a
metastatic cancer is the ability of a precancerous or cancerous
cell to detach from primary site of disease and establish a novel
colony of growth at a secondary site. The ability of a cell to
invade peripheral sites is reflective of a potential for a
cancerous state. Loss of invasiveness may be measured by a variety
of techniques known in the art including, for example, induction of
E-cadherin-mediated cell-cell adhesion. Such E-cadherin-mediated
adhesion can result in phenotypic reversion and loss of
invasiveness (Hordijk et al., 1997, Science 278:1464-66).
[1987] Loss of invasiveness may further be examined by inhibition
of cell migration. A variety of 2-dimensional and 3-dimensional
cellular matrices are commercially available
(Calbiochem-Novabiochem Corp. San Diego, Calif.). Cell migration
across or into a matrix may be examined by microscopy, time-lapsed
photography or videography, or by any method in the art allowing
measurement of cellular migration. In a related embodiment, loss of
invasiveness is examined by response to hepatocyte growth factor
(HGF). HGF-induced cell scattering is correlated with invasiveness
of cells such as Madin-Darby canine kidney (MDCK) cells. This assay
identifies a cell population that has lost cell scattering activity
in response to HGF (Hordijk et al., 1997, Science 278:1464-66).
[1988] Alternatively, loss of invasiveness may be measured by cell
migration through a chemotaxis chamber (Neuroprobe/ Precision
Biochemicals Inc. Vancouver, BC). In such assay, a chemo-attractant
agent is incubated on one side of the chamber (e.g., the bottom
chamber) and cells are plated on a filter separating the opposite
side (e.g., the top chamber). In order for cells to pass from the
top chamber to the bottom chamber, the cells must actively migrate
through small pores in the filter. Checkerboard analysis of the
number of cells that have migrated may then be correlated with
invasiveness (see e.g., Ohnishi, T., 1993, Biochem. Biophys. Res.
Commun.193:518-25).
[1989] The Pyrrole-Type compounds can also be demonstrated to
inhibit tumor formation in vivo. A vast number of animal models of
hyperproliferative disorders, including tumorigenesis and
metastatic spread, are known in the art (see Table 317-1, Chapter
317, "Principals of Neoplasia," in Harrison's Principals of
Internal Medicine, 13th Edition, Isselbacher et al., eds.,
McGraw-Hill, New York, p. 1814, and Lovejoy et al., 1997, J.
Pathol. 181:130-135). Specific examples include for lung cancer,
transplantation of tumor nodules into rats (Wang et al., 1997, Ann.
Thorac. Surg. 64:216-219) or establishment of lung cancer
metastases in SCID mice depleted of NK cells (Yono and Sone, 1997,
Gan To Kagaku Ryoho 24:489-494); for colon cancer, colon cancer
transplantation of human colon cancer cells into nude mice (Gutman
and Fidler, 1995, World J. Surg. 19:226-234), the cotton top
tamarin model of human ulcerative colitis (Warren, 1996, Aliment.
Pharmacol. Ther. 10 Supp 12:45-47) and mouse models with mutations
of the adenomatous polyposis tumor suppressor (Polakis, 1997,
Biochim. Biophys. Acta 1332:F127-F147); for breast cancer,
transgenic models of breast cancer (Dankort and Muller, 1996,
Cancer Treat. Res. 83:71-88; Amundadittir et al., 1996, Breast
Cancer Res. Treat. 39:119-135) and chemical induction of tumors in
rats (Russo and Russo, 1996, Breast Cancer Res. Treat. 39:7-20);
for prostate cancer, chemically-induced and transgenic rodent
models, and human xenograft models (Royai et al., 1996, Semin.
Oncol. 23:35-40); for genitourinary cancers, induced bladder
neoplasm in rats and mice (Oyasu, 1995, Food Chem. Toxicol
33:747-755) and xenografts of human transitional cell carcinomas
into nude rats (Jarrett et al., 1995, J. Endourol. 9:1-7); and for
hematopoietic cancers, transplanted allogeneic marrow in animals
(Appelbaum, 1997, Leukemia 11 (Suppl. 4):S15-S17). Further, general
animal models applicable to many types of cancer have been
described, including, but not restricted to, the p53-deficient
mouse model (Donehower, 1996, Semin. Cancer Biol. 7:269-278), the
Min mouse (Shoemaker et al., 1997, Biochem. Biophys. Acta,
1332:F25-F48), and immune responses to tumors in rat (Frey, 1997,
Methods, 12:173-188).
[1990] For example, a Pyrrole-Type compound can be administered to
a test animal, preferably a test animal predisposed to develop a
type of tumor, and the test animal subsequently examined for a
decreased incidence of tumor formation in comparison with controls
not administered the Pyrrole-Type compound. Alternatively, a
Pyrrole-Type compound can be administered to test animals having
tumors (e.g., animals in which tumors have been induced by
introduction of malignant, neoplastic, or transformed cells, or by
administration of a carcinogen) and subsequently examining the
tumors in the test animals for tumor regression in comparison to
controls not administered the Pyrrole-Type compound.
[1991] 5.17.1. Treatment of Prevention of Cancer or a Neoplastic
Disease in Combination with Chemotherapy or Radiotherapy
[1992] Cancer or a neoplastic disease, including, but not limited
to, neoplasms, tumors, metastases, or any disease or disorder
characterized by uncontrolled cell growth, can be treated or
prevented by administration of a composition comprising a
pharmaceutically acceptable carrier and a Pyrrole-Type compound or
a pharmaceutically acceptable salt thereof. The compositions can
comprise one or more Pyrrole-Type compounds, or a pharmaceutically
acceptable salt thereof.
[1993] In certain embodiments, one or more Pyrrole-Type compounds
of the invention are used to treat or prevent cancer or neoplastic
disease in combination with one or more anti-cancer,
chemotherapeutic agents including, but not limited to,
methotrexate, taxol, mercaptopurine, thioguanine, hydroxyurea,
cytarabine, cyclophosphamide, ifosfamide, nitrosoureas, cisplatin,
carboplatin, mitomycin, dacarbazine, procarbizine, etoposides,
campathecins, bleomycin, doxorubicin, idarubicin, daunorubicin,
dactinomycin, plicamycin, mitoxantrone, asparaginase, vinblastine,
vincristine, vinorelbine, paclitaxel, and docetaxel. In a preferred
embodiment, one or more Pyrrole-Type compound of the invention is
used to treat or prevent cancer or neoplastic disease in
combination with one or more chemotherapeutic or other anti-cancer
agents including, but not limited to, those presented in Table
1.
2TABLE 1 CHEMOTHERAPEUTICS AND OTHER ANTI-CANCER AGENTS Radiation:
.gamma.-radiation Alkylating agents Nitrogen mustards:
cyclophosphamide Ifosfamide trofosfamide Chlorambucil Nitrosoureas:
carmustine (BCNU) Lomustine (CCNU) Alkylsulphonates busulfan
Treosulfan Triazenes: Dacarbazine Platinum containing compounds:
Cisplatin carboplatin Plant Alkaloids Vinca alkaloids: vincristine
Vinblastine Vindesine Vinorelbine Taxoids: paclitaxel Docetaxol DNA
Topoisomerase Inhibitors Epipodophyllins: etoposide Teniposide
Topotecan 9-aminocamptothecin campto irinotecan crisnatol
mytomycins: mytomycin C Mytomycin C Anti-metabolites Anti-folates:
DHFR inhibitors: methotrexate Trimetrexate IMP dehydrogenase
Inhibitors: mycophenolic acid Tiazofurin Ribavirin EICAR
Ribonuclotide reductase Inhibitors: hydroxyurea deferoxamine
Pyrimidine analogs: Uracil analogs 5-Fluorouracil Floxuridine
Doxifluridine Ratitrexed Cytosine analogs cytarabine (ara C)
Cytosine arabinoside fludarabine Purine analogs: mercaptopurine
Thioguanine Hormonal therapies: Receptor antagonists:
Anti-estrogens Tamoxifen Raloxifene megestrol LHRH agonists:
goscrclin Leuprolide acetate Anti-androgens: flutamide bicalutamide
Retinoids/Deltoids Vitamin D3 analogs: EB 1089 CB 1093 KH 1060
Photodyamic therapies: vertoporfin (BPD-MA) Phthalocyanine
photosensitizer Pc4 Demethoxy-hypocrellin A (2BA-2-DMHA) Cytokines:
Interferon-.alpha. Interferon-.gamma. Tumor necrosis factor Others:
Isoprenylation inhibitors: Lovastatin Dopaminergic neurotoxins:
1-methyl-4-phenylpyridinium ion Cell cycle inhibitors:
staurosporine Actinomycins: Actinomycin D Dactinomycin Bleomycins:
bleomycin A2 Bleomycin B2 Peplomycin Anthracyclines: daunorubicin
Doxorubicin (adriamycin) Idarubicin Epirubicin Pirarubicin
Zorubicin Mitoxantrone MDR inhibitors: verapamil Ca.sup.2+ ATPase
inhibitors: thapsigargin
[1994] In other embodiments, a composition comprising one or more
Pyrrole-Type compounds is administered along with radiation therapy
and/or with one or a combination of chemotherapeutic agents,
preferably with one or more chemotherapeutic agents with which
treatment of the cancer has not been found to be refractory. The
Pyrrole-Type compound can be administered to a patient that has
also undergone surgery as treatment for the cancer.
[1995] In another specific embodiment, the invention provides a
method to treat or prevent cancer that has shown to be refractory
to treatment with a chemotherapy and/or radiation therapy.
[1996] In a specific embodiment, a composition comprising one or
more Pyrrole-Type compounds is administered concurrently with
chemotherapy or radiation therapy. In another specific embodiment,
chemotherapy or radiation therapy is administered prior or
subsequent to administration of a present composition, preferably
at least an hour, five hours, 12 hours, a day, a week, a month,
more preferably several months (e.g., up to three months),
subsequent to administration of a therapeutic of the invention.
[1997] The chemotherapy or radiation therapy administered
concurrently with, or prior or subsequent to, the administration of
a present composition can be accomplished by any method known in
the art. The chemotherapeutic agents are preferably administered in
a series of sessions, any one or a combination of the
chemotherapeutic agents listed above can be administered. With
respect to radiation therapy, any radiation therapy protocol can be
used depending upon the type of cancer to be treated. For example,
but not by way of limitation, x-ray radiation can be administered;
in particular, high-energy megavoltage (radiation of greater that 1
MeV energy) can be used for deep tumors, and electron beam and
orthovoltage x-ray radiation can be used for skin cancers.
Gamma-ray emitting radioisotopes, such as radioactive isotopes of
radium, cobalt and other elements, may also be administered to
expose tissues to radiation.
[1998] Additionally, the invention provides methods of treatment of
cancer or neoplastic disease with a present composition as an
alternative to chemotherapy or radiation therapy where the
chemotherapy or the radiation therapy has proven or may prove too
toxic, e.g., results in unacceptable or unbearable side effects,
for the subject being treated. The subject being treated with the
present compositions may, optionally, be treated with other cancer
treatments such as surgery, radiation therapy or chemotherapy,
depending on which treatment is found to be acceptable or
bearable.
[1999] 5.17.2. Cancer and Neoplastic Disease Treatable or
Preventable
[2000] Cancers or neoplastic diseases and related disorders that
can be treated or prevented by administration of the present
compositions include but are not limited to those listed in Table 2
(for a review of such disorders, see Fishman et al., 1985,
Medicine, 2d Ed., J.B. Lippincott Co., Philadelphia):
3TABLE 2 CANCERS AND NEOPLASTIC DISORDERS Leukemia acute leukemia
acute lymphocytic leukemia acute myelocytic leukemia myeloblastic
promyelocytic myelomonocytic monocytic erythroleukemia chronic
leukemia chronic myelocytic (granulocytic) leukemia chronic
lymphocytic leukemia Polycythemia vera Lymphoma Hodgkin's disease
non-Hodgkin's disease Multiple myeloma Waldenstrom's
macroglobulinemia Heavy chain disease Solid tumors sarcomas and
carcinomas fibrosarcoma myxosarcoma liposarcoma chondrosarcoma
osteogenic sarcoma chordoma angiosarcoma endotheliosarcoma
lymphangiosarcoma lymphangioendotheliosarcoma synovioma
mesothelioma Ewing's tumor leiomyosarcoma rhabdomyosarcoma colon
carcinoma pancreatic cancer breast cancer ovarian cancer prostate
cancer squamous cell carcinoma basal cell carcinoma adenocarcinoma
sweat gland carcinoma sebaceous gland carcinoma papillary carcinoma
papillary adenocarcinomas cystadenocarcinoma medullary carcinoma
bronchogenic carcinoma renal cell carcinoma hepatoma bile duct
carcinoma choriocarcinoma seminoma embryonal carcinoma Wilms' tumor
cervical cancer uterine cancer testicular tumor lung carcinoma
small cell lung carcinoma bladder carcinoma epithelial carcinoma
glioma astrocytoma medulloblastoma craniopharyngioma ependymoma
pinealoma hemangioblastoma acoustic neuroma oligodendroglioma
meningioma melanoma neuroblastoma retinoblastoma
[2001] In specific embodiments, cancer, malignancy or
dysproliferative changes (such as metaplasias and dysplasias), or
hyperproliferative disorders, are treated or prevented in the
ovary, breast, colon, lung, skin, pancreas, prostate, bladder, or
uterus. In other specific embodiments, sarcoma, melanoma, or
leukemia is treated or prevented.
[2002] In a highly preferred embodiment, the present compositions
are used to treat or prevent cancers including prostate (more
preferably hormone-insensitive), Neuroblastoma, Lymphoma
(preferably follicular or Diffuse Large B-cell), Breast (preferably
Estrogen-receptor positive), Colorectal, Endometrial, Ovarian,
Lymphoma (preferably non-Hodgkin's), Lung (preferably Small cell),
or Testicular (preferably germ cell).
[2003] In a preferred embodiment, the present compositions are used
to inhibit the growth of a cell derived from a cancer or neoplasm
such as prostate (more preferably hormone-insensitive),
Neuroblastoma, Lymphoma (preferably follicular or Diffuse Large
B-cell), Breast (preferably Estrogen-receptor positive),
Colorectal, Endometrial, Ovarian, Lymphoma (preferably
non-Hodgkin's), Lung (preferably Small cell), or Testicular
(preferably germ cell).
[2004] In specific embodiments of the invention, the present
compositions are used to inhibit the growth of a cell, said cell
being derived from a cancer or neoplasm in Table 2 or herein.
[2005] 5.17.3. Demonstration of Inhibition of Viruses and Viral
Infections
[2006] The Pyrrole-Type compounds may be demonstrated to inhibit
the replication or infectivity of a virus or a virus-infected cell
in vitro or in vivo using a variety of assays known in the art, or
described herein. In certain embodiments, such assays may use cells
of a cell line, or cells from a patient. In specific embodiments,
the cells may be infected with a virus prior to the assay, or
during the assay. The cells may be contacted with a virus. In
certain other embodiments, the assays may employ cell-free viral
cultures.
[2007] In one embodiment, a Pyrrole-Type compound is demonstrated
to have activity in treating or preventing viral disease by
contacting cultured cells that exhibit an indicator of a viral
reaction (e.g., formation of inclusion bodies) in vitro with the
Pyrrole-Type compound, and comparing the level of said indicator in
the cells contacted with the Pyrrole-Type compound with said level
of said indicator in cells not so contacted, wherein a lower level
in said contacted cells indicates that the Pyrrole-Type compound
has activity in treating or preventing viral disease. Cell models
that can be used for such assays include, but are not limited to,
viral infection of T lymphocytes (Selin et al., 1996, J. Exp. Med.
183:2489-2499); hepatitis B infection of dedifferentiated hepatoma
cells (Raney et al., 1997, J. Virol. 71:1058-1071); viral infection
of cultured salivary gland epithelial cells (Clark et al., 1994,
Autoimmunity 18:7-14); synchronous HIV-1 infection of CD4.sup.+
lymphocytic cell lines (Wainberg et al., 1997, Virology
233:364-373); viral infection of respiratory epithelial cells
(Stark et al., 1996, Human Gene Ther. 7:1669-1681); and
amphotrophic retroviral infection of NIH-3T3 cells (Morgan et al.,
1995, J. Virol. 69:6994-7000).
[2008] In another embodiment, a Pyrrole-Type compound can be
demonstrated to have activity in treating or preventing viral
disease by administering said Pyrrole-Type compound to a test
animal having symptoms of a viral infection, such as characteristic
respiratory symptoms in animal models, or which test animal does
not exhibit a viral reaction and is subsequently challenged with an
agent that elicits an viral reaction, and measuring the change in
the viral reaction after the administration of said Pyrrole-Type
compound, wherein a reduction in said viral reaction or a
prevention of said viral reaction indicates that the Pyrrole-Type
compound has activity in treating or preventing viral disease.
Animal models that can be used for such assays include, but are not
limited to, guinea pigs for respiratory viral infections (Kudlacz
and Knippenberg, 1995, Inflamm. Res. 44:105-110); mice for
influenza virus infection (Dobbs et al., 1996, J. Immunol.
157:1870-1877); lambs for respiratory syncitial virus infection
(Masot et al., 1996, Zentralbl. Veterinarmed. 43:233-243); mice for
neurotrophic virus infection (Barna et al., 1996, Virology
223:331-343); hamsters for measles infection (Fukuda et al., 1994,
Acta Otolaryngol. Suppl (Stockh.) 514:111-116); mice for
encephalomyocarditis infection (Hirasawa et al., 1997, J. Virol.
71:4024-4031); and mice for cytomegalovirus infection (Orange and
Biron, 1996, J. Immunol. 156:1138-1142). In certain embodiments of
the invention more than one Pyrrole-Type compound is administered
to a test animal, virus, or viral-infected cell.
[2009] 5.17.4. Viruses and Viral Infections
[2010] Viruses and viral infections that can be treated or
prevented by administration of a composition of the invention
include but are not limited to those listed in Table 3 including,
but not limited to, DNA viruses such as hepatitis type B and
hepatitis type C virus; parvoviruses, such as adeno-associated
virus and cytomegalovirus; papovaviruses such as papilloma virus,
polyoma viruses, and SV40; adenoviruses; herpes viruses such as
herpes simplex type I (HSV-I), herpes simplex type II (HSV-II), and
Epstein-Barr virus; poxviruses, such as variola (smallpox) and
vaccinia virus; and RNA viruses, such as human immunodeficiency
virus type I (HIV-I), human immunodeficiency virus type II
(HIV-II), human T-cell lymphotropic virus type I (HTLV-I), human
T-cell lymphotropic virus type II (HTLV-II), influenza virus,
measles virus, rabies virus, Sendai virus, picomaviruses such as
poliomyelitis virus, coxsackieviruses, rhinoviruses, reoviruses,
togaviruses such as rubella virus (German measles) and Semliki
forest virus, arboviruses, and hepatitis type A virus.
[2011] In a preferred embodiment of the invention, the compositions
of the invention are used to treat or prevent a viral infection
associated with a virus as listed in Table 3. In another preferred
embodiment, the compositions of the invention are used inhibit the
replication or infectivity of a virus listed in Table 3. In yet
another preferred embodiment, one or more Pyrrole-Type compounds of
the invention are used inhibit the growth of a cell infected with a
virus listed in Table 3.
4 TABLE 3 Herpesviruses: EBV HHV-8 (KSHV) Herpesvirus saimiri
Adenoviruses: All strains Retroviruses: HIV-1 and 2 HTLV-I Human
Papillomaviruses: HPV - all strains Birnaviruses: Infectious
pancreatic necrosis virus Other: African Swine Fever virus (all
strains)
[2012] 5.17.5. Immunosuppression and Treatment and Prevention of
Autoimmune Diseases
[2013] Many human diseases are characterized by excessive or
inappropriate immune responses. Examples of such diseases include
allergic reactions, auto-immune diseases, and rejection in
allogeneic transplants, also known as "graft rejection." Allogeneic
tissues and organs are tissues and organs from a genetically
different member of the same species. "Graft rejection" occurs when
a body's immune system attacks and destroys the transplanted
tissue, for example in a heart, kidney, or bone marrow transplant,
contains allogeneic. In these diseases, suppression of the immune
response in a patient is beneficial, since the individual's
immunological response causes more damage or discomfort than the
invading microbes or foreign material. It is now recognized that
immunosuppressive therapy is appropriate for treating each of these
disorders (Blood Reviews, 1995, 9:117-133). The Pyrrole-Type
compounds of the invention are useful for causing immunosuppression
in a patient in need thereof. Accordingly, the Pyrrole-Type
compounds of the invention are useful for treating or preventing
allergies, autoimmune diseases, and rejection associated with an
allogeneic transplant or "graft rejection."
[2014] In allergy, the immune system is hyper-responsive to
otherwise harmless environmental antigens. Suppressing the immune
system can alleviate the discomfort associated with the a body's
excessive reaction to an otherwise harmless environmental antigen.
Accordingly, the Pyrrole-Type compounds of the invention are useful
for treating or preventing an allergy.
[2015] In autoimmune disease, the immune system attacks normal
tissues. The immunological mechanisms become sensitized to some
part of the individual's own body causing interference with or even
destruction of that part. The ability to distinguish between "self"
and "not self" antigens, which is vital to the functioning of the
immune system as a specific defense against invading
microorganisms, is impaired and the body begins to destroy itself.
"Non-self" antigens are those antigens on substances in the body
that are detectably different from or foreign to the body's own
constituents. "Self" antigens are those antigens that are not
detectably different from or foreign to the body's own
constituents. In other cases, autoimmunity occurs as the result of
trauma to an area usually not exposed to lymphocytes such as neural
tissue or the lens of the eye. When the tissues in these areas
become exposed to lymphocytes, their surface proteins can act as
antigens and trigger the production of antibodies and cellular
immune responses that then begin to destroy those tissues. Other
autoimmune diseases develop after exposure of the individual to
antigens that are antigenically similar to, that is cross-react
with, the individual's own tissue. Rheumatic fever is an example of
this type of disease, in which the antigen of a streptococcal
bacterium, which causes rheumatic fever, is cross-reactive with
parts of the human heart. Antibodies cannot differentiate between
the bacterial antigens and the heart muscle antigens and
accordingly, can destroy cells having either of those antigens.
Suppression of the immune system would be useful for minimizing or
eliminating the effects of autoimmune diseases. Accordingly, the
Pyrrole-Type compounds of the invention are useful for treating or
preventing autoimmune diseases.
[2016] Examples of autoimmune diseases that can be treated or
prevented by administering the Pyrrole-Type compounds of the
invention, include, but are not limited to, rheumatoid arthritis,
insulin-dependent diabetes mellitus (which involves the autoimmune
destruction of the .beta.-cells of the islets of Langerhans which
are responsible for the secretion of insulin), certain hemolytic
anemias, rheumatic fever, thyroiditis, ulceractive colitis,
myesthethia gravis, glomerulonephritis, allergic encephalomyelitis,
continuing nerve and liver destruction that follows viral
hepatitis, multiple sclerosis, systemic lupus erythematosus,
juvenile diabetes, autoimmune haemolytic anaemia, psoriasis,
idiopathic thrombocytopenic purpura, active chronic hepatitis,
idiopathic leucopenia, primary biliary cirrhosis, thyrotoxicosis,
dermatomyositis, discoid lupus erythematosus, psoriatic arthritis,
regional enteritis, nephrotic syndrome, lupus nephritis, lupoid
hepatitis, Sjogren's syndrome, Goodpasture's syndrome, Wegener's
granulomatosis, scleroderma, Sezary's disease, uveitis, and mumps
orchitis. In a more preferred embodiment, the Pyrrole-Type
compounds of the invention are used to treat or prevent rheumatoid
arthritis, systemic lupus erythmatosus, juvenile diabetis,
myesthethia gravis, multiple sclerosis, or psoriasis.
[2017] Similarly, when the body rejects allogenic transplants and
suffers "graft rejection," it would be extremely useful to suppress
the immune response in order to prevent the rejection of useful
transplanted tissue or organs. Suppression of the immune response
is useful for preventing rejection of allograft tissues and organs.
Accordingly, the Pyrrole-Type compounds of the invention are useful
for treating or preventing the rejection associated with allogeneic
tissue and organ transplants.
6. EXAMPLES
6.1. Preparation of Compound 79
[2018] The preparation of Compound 79 generally involved the
preparation of the boronic acid 8 of the 1-Boc pyrrole (73) and the
corresponding triflate 78 (see Scheme 1 below). The Suzuki coupling
of those two intermediates gave the desired product Compound 79
(4-methoxy-5-(1H-indol-2yl-methylene)-2,2'-bi-1H-pyrrole). 63
[2019] 6.1.1. (1-tert-Butoxycarbonylpyrrol-2-yl)boronic acid,
(8)
[2020] A solution of anhydrous diisopropylamine (3.35 mL, 23.9
mmol) was prepared in 100 mL of anhydrous THF and cooled at
-78.degree. C. A solution of 2.5 M of n-butyllithium (10.5 mL, 26.3
mmol) was slowly added to the THF solution over 10 minutes. The
resulting mixture was stirred at -78.degree. C. for 15 minutes and
was then warmed to 0.degree. C. for 15 minutes. The resulting
mixture was cooled again at -78.degree. C. and the tert-butyl
1-pyrrole carboxylate (73) (4.00 mL, 23.9 mmol) was added. The
resulting solution was stirred for 1 hour at -78.degree. C. and
trimethyl borate (2.70 mL, 23.9 mmol) was added. The resulting
solution was allowed to warm up to room temperature overnight. 20
mL of dilute HCl (0.25N) was added to the room temperature
solution, which was stirred at room temperature for 15 minutes. The
THF was removed under reduced pressure. The residue was extracted
with diethyl ether (3.times.100 mL). The organic layer was dried
over sodium sulfate, filtered and then concentrated in vacuo.
Trituration with hexane (10 mL) and filtration gave the Compound 8
as beige solid (2.56 g, 51%). .sup.1H NMR (500 MHz, CDCl.sub.3):
.delta. (ppm), 7.71 (s, 2H); 7.48 (t, 1H, J=2 Hz); 7.15 (t, 1H,
J=1.8 Hz); 6.29 (t, 1H, J=3.1 Hz); 1.65 (3, 9H). .sup.13C NMR (500
MHz, CDCl.sub.3): .delta. (ppm), 153.22; 129.67; 127.92; 112.96;
86.47; 28.84.
[2021] 6.1.2. Indole 2-carboxaldehyde, (75)
[2022] Indole (74) (1.00 g, 8.54 mmol) was dissolved in 50 mL of
dry THF. The resulting solution was cooled at -78.degree. C. A
solution of 2.5 M of n-butyllithium (3.80 mL, 9.39 mmol) was slowly
added to the THF solution and was stirred for 30 min. Carbon
dioxide was passed through the reaction mixture over 10 min. The
resulting solution was allowed to warm to room temperature. The
excess of carbon dioxide was removed under reduced pressure while
the solution was concentrated to 25 mL. 50 mL of dry THF was added
to the concentrated solution, which was cooled again to -78.degree.
C. A solution of 1.7 M of tert-butyllithium (5.00 mL, 8.54 mmol)
was slowly added to the THF solution, which was stirred at
-78.degree. C. for 1 hour. Anhydrous N,N-dimethylformamide (0.83
mL, 8.5 mmol) was added to the solution. The resulting mixture was
warmed to room temperature over a period of 1.5 hours. Water (10
mL) was added and the mixture was stirred for 15 min. Diethyl ether
was added. The organic layer was washed with brine (3.times.). The
organic layer was dried over magnesium sulfate, filtered and
concentrated in vacuo. The solid was purified over silica gel using
80/20 hexanes/ethyl acetate as eluent to give Compound 75, (0.7129
g, 58%). .sup.1H NMR (500 MHz, CDCl.sub.3): d (ppm), 9.88 (s, 1H);
7.77 (d, 1H, J=8.1 Hz); 7.48 (d, 1H, J=8.3 Hz); 7.41 (t, 1H, J=7.0
Hz); 7.3 (s, 1H); 7.20 (t, 1H, J=7.4 Hz). .sup.13C NMR (500 MHz,
CDCl.sub.3): .delta. (ppm), 182.89; 138.80; 136.87; 128.25; 124.37;
122.20; 115.60; 113.28.
[2023] 6.1.3.
4-Methoxy-5-(1H-indol-2-yl-methylene)-1,5-dihydro-2-pyrrol-2- -one,
(77)
[2024] To a solution of indole 2-carboxaldehyde (75) (0.1500 g,
1.033 mmol) and 4-methoxy-3-pyrrolin-2-one (76) (0.2330 g, 2.060
mmol) in DMSO (10 mL) were added 5 mL of a solution of 2N NaOH. The
resulting mixture was stirred overnight at 60.degree. C. The
stirred mixture was allowed to cool to room temperature and then
poured into 250 mL of water. The resulting yellow solid precipitate
was filtered and dried in a dessicator to give Compound 77 (0.1257
g, 51%). .sup.1H NMR (500 MHz, DMSO): .delta. (ppm), 11.14 (s, 1H);
9.69 (s, 1H); 7.49 (d, 1H, J=7.9 Hz); 7.34 (d, 1H, 8.1 Hz); 7.11
(t, 1H, J=7.4 Hz); 6.99 (m. 2H); 6.25 (s, 1H); 5.35 (s, 1H) 3.89
(s, 3H). .sup.13C NMR (500 MHz, DMSO): .delta. (ppm) 172.47;
168.25; 138.41; 133.78; 131.53; 129.92; 123.80; 121.60; 120.98;
112.46; 105.91; 98.22; 93.71; 59.95.
[2025] 6.1.4.
2-trifluoromethanesulfonyloxy-4-methoxy-5-(1H-indol-2-yl-met-
hylene)-1H-pyrrole, (78)
[2026] To a solution of 77 (8.4 mg, 35 mol) in 5 mL of dry
dichloromethane was added 1.1 equivalent of triluoromethanesulfonic
anhydride at 0.degree. C. The resulting solution was stirred at
0.degree. C. for 5 min and was then poured into 5 mL of saturated
aqueous NaHCO.sub.3. The organic layer was dried over sodium
sulfate, filtered and rapidly concentrated to give the crude
triflate 78, which was used immediately, without further
purification. .sup.1H NMR (500 MHz, CD.sub.2Cl.sub.2): .delta.
(ppm), 11.15 (s 1H); 7.72 (m, 3H); 7.61 (s, 1H); 7.50 (m, 1H), 7.20
(m, 1H); 6.01 (s, 1H); 4.16 (s, 3H).
[2027] 6.1.5.
4-methoxy-5-(1H-indol-2-yl-methylene)-2,2'-bi-1H-pyrrole (79)
[2028] The crude triflate 78 was mixed with about 3 equivalent of
boronic acid 8, 8 equivalents of potassium carbonate and about 0.1
equivalent of tetrakistriphenylphosphine palladium under argon.
Anhydrous 1,4-dioxane (10 mL) was added to the reaction mixture,
and it was heated at 90.degree. C. in a sand bath. After three
hours, the mixture was cooled and added to ethyl acetate (100 mL).
The organic layer was washed with brine (3.times.100 mL) and was
then dried over sodium sulfate, filtered and concentrated in vacuo.
The resulting crude mixture was passed through a short column of
neutral alumina using 50/50 hexanes/ethyl acetate as an eluent. The
relevant fractions were combined and concentrated, and the
resulting crude product was purified using a preparative plate of
neutral alumina and eluted using 80/20 hexanes/ethyl acetate. The
alumina band containing Compound 79 was washed with ethyl acetate
and concentrated to provide the Compound 79 as a red dark solid (2
mg, 20%).(500 MHz, CD.sub.3OD) : .delta. (ppm), 7.55 (m, 2H); 7.20
(t, 1H); 7.13 (s, 1H); 7.03 (t, 1H); 6.90 (s, 1H), 6.88 (s, 1H);
6.85 (s, 1H); 6.32 (s, 1H), 6.17 (s, 1H); 3.97 (s, 3H). MS (M+H):
290.0.
6.2. In Vitro Activity of Compound 79
(4-METHOXY-5-(1H-INDOL-2YL-METHYLENE- )-2,2'-BI-1H-PYRROLE)
[2029] Compound 79's selective toxicity to cancer cells by
apoptosis is shown below.
[2030] 6.2.1. Compound 79 Selectively Affects Cancer Cell
Viability
[2031] Without being bound by theory, a marked decrease in
mitochondrial ATP production is associated with progression towards
irreversible cell dysfunction and death. To determine the effect of
compound 79
(4-methoxy-5-(1H-indol-2yl-methylene)-2,2'-bi-1H-pyrrole) on cell
viability, the cellular ATP levels were measured following compound
79 treatment. H1299 non-small cell lung carcinoma cells, C33A
cervical carcinoma cells, Mrc-5 normal lung fibroblasts (American
Type Culture Collection, Manassas, Va. USA) and HMEC normal mammary
epithelial cells (Clonetics San Diego, Calif., USA) were cultured
in the media recommended by the American Type Culture Collection.
The four cells lines were plated in 96-well microtiter plates
(PerkinElmer Life Sciences Inc, Boston, Mass. USA) at a density
that allowed them to reach confluence after 4 days of growth. One
day after plating, the cells were treated with 10 .mu.M Compound
79. 50 mM stock solutions of Compound 79 were prepared in dimethyl
sulfoxide (Sigma-Aldrich Inc., St. Louis, Mo. USA), diluted in
media and then added to the cells. The total dimethyl sulfoxide on
the cells was 1%. After 3 days of incubation, the ATP levels in the
cells were quantified using the luminescent VIALIGHT detection
system (Bio Whittaker, MD, USA). The results were plotted relative
to untreated control cells, which were set at 100 (FIG. 1).
[2032] The results shown in FIG. 1 demonstrate that a 72-hour
treatment with 10 .mu.M of compound 79 lowered the ATP levels of
the cancer cell lines H1299 and C33A to a greater extent than the
ATP levels of the normal cell lines HMEC and MRC-5. Therefore,
Compound 79 is selectively toxic to cancer cells, particularly
non-small cell lung carcinoma and cervical carcinoma cells.
[2033] 6.2.2. Compound 79 Selectively Induces Apoptosis in Cancer
Cells
[2034] To demonstrate the ability of the Compound 79 to trigger
caspase activation, and, therefore, apoptosis, lysates of cells
treated with various concentrations of Compound 79 were prepared.
H1299 non-small cell lung carcinoma cells, C33A cervical carcinoma
cells, Mrc-5 normal lung fibroblasts (American Type Culture
Collection, Manassas, Va. USA) and HMEC normal mammary epithelial
cells (Clonetics San Diego, Calif., USA) were maintained in media
recommended by the American Type Culture Collection. Cells were
harvested and suspended at 2.5-5.times.10.sup.5 cells/ml in media.
A 45 .mu.L aliquot of cell suspension was added to each well of a
96-well microtiter plate (PerkinElmer Life Sciences Inc, Boston,
Mass. USA). Cells were incubated overnight in a 5% CO.sub.2-95%
humidity incubator at 37.degree. C. and then, 5 .mu.L of a 10%
dimethyl sulfoxide (Sigma-Aldrich Inc., St. Louis, Mo. USA)
solution containing various concentrations of Compound 79 or 5
.mu.L of 10% dimethyl sulfoxide (solvent control) were added. The
plates were further incubated for 16 hr. Cells were lysed in lysis
buffer (50 mM Hepes pH 7.4; 0.1% Chaps; 10 mM EDTA; 10 mM DTT) and
set aside for caspase activity testing.
[2035] To demonstrate the caspase activity in the cell lysates,
0.35 .mu.g of N-terminal biotinylated EGKRKGDEVDGVPDRRASV peptide
(Phoenix Pharmaceuticals Inc, Belmont, Calif. USA) were labeled
with 1 mCi of [.sup.32P]-.gamma.ATP (PerkinElmer Life Sciences Inc,
Boston, Mass. USA) using 250 units of Protein Kinase A catalytic
subunit from bovine heart (Sigma-Aldrich Inc., St. Louis, Mo. USA)
in 500 .mu.L of HMK buffer (20 mM pH 7.5 Tris-HCl; 0.1 M NaCl; 12
mM MgCl.sub.2; 1 mM DTT) at 37.degree. C. for one hour. The
reaction was then filtered using Sephadex G-10 Poly-Prep
chromatography column (Amersham Biosciences, Inc, Piscataway, N.J.,
USA). The labeled peptide was coupled to 1.25 mL of streptavidin
sepharose beads (Amersham Biosciences, Inc, Piscataway, N.J., USA)
during 15 minutes at room temperature on a rotary mixer. The beads
were washed seven times with 6 mL of 0.5 M NaCl in PBS and
resuspended in a total volume of 7.25 mL of 0.5 M NaCl in PBS
solution to which 9 mL of RPMI 1640 media (Bio Whittaker, MD, USA)
was added. 96-well 0.45 .mu.m MultiScreen-HV filter plates
(Millipore, Bedford, Mass. USA) were then pre-wetted with 200 .mu.L
of 0.5 M NaCl in PBS and 40 .mu.L of beads suspension was added to
each well. Each well was washed five times with 200 .mu.L of 0.5 M
NaCl in PBS. In each well, 50 .mu.L of cell lysate was added
together with 12.5 .mu.L of 0.5 M NaCl in 30% glycerol solution to
each well. The plates were incubated at 30.degree. C. with shaking
at 220 rpm overnight. The next day, the filter plates containing
the beads and the extract were centrifuged into of 96-well sample
plates (PerkinElmer Life Sciences Inc, Boston, Mass. USA)
containing 100 .mu.L of Optiphase SuperMix liquid scintillant fluid
(PerkinElmer Life Sciences Inc, Boston, Mass. USA) in each well and
centrifuged at 1500 rpm for 10 minutes at room temperature. The
number of radioactive counts per minute (cpm) in each well of the
sample plate was measured using a liquid scintillation counter
(PerkinElmer Life Sciences Inc, Boston, Mass. USA). The potency of
caspase cascade activation was determined by the percentage
increase in cpm in wells compared to cells treated only with
dimethyl sulfoxide. Values 1.5-fold higher (150%) than control were
considered positive and indicated that the compound triggered
caspase activation in the cells, and, therefore, apoptosis.
[2036] The Compound 79 concentration required to positively
activate caspases and, therefore, cause apoptosis in cancer cell
lines was 250 .mu.M and 125 .mu.M for H1299- and C3AA-cancer cell
lines, respectively (Table 4). However, in normal cell lines
concentrations of greater than 500 .mu.M are required to obtain
such caspase activation (Table 4). These results demonstrate that
caspases were activated in cancer cell lines but not in the normal
cell line following 16 hours incubation with Compound 79.
Accordingly, Compound 79 induces apoptosis selectively in cancer
cells, particularly non-small cell lung carcinoma and cervical
carcinoma cells.
5 TABLE 4 Concentration Required for Positive Caspase Activation
(.mu.M) Cancer Normal Cell Lines Cell Lines Compound H1299 C33A
HMEC MRC5 79 (4-methoxy-5- 250 125 >500 >500 (1H-indol-2yl-
methylene)-2,2'-bi- 1H-pyrrole)
[2037] The above example shows that an illustrative Pyrrole-Type
Compound is selectively cytotoxic to cancer cells. This example
also demonstrates that the Pyrrole-Type Compounds are useful for
the treatment and prevention of cancer, particularly lung carcinoma
and cervical carcinoma. This example further demonstrates that the
Pyrrole-Type Compounds are useful for the inhibition of cancerous
growth, particularly lung carcinoma growth and cervical carcinoma
growth.
[2038] The present invention is not to be limited in scope by the
specific embodiments disclosed in the examples which are intended
as illustrations of a few aspects of the invention and any
embodiments that are functionally equivalent are within the scope
of this invention. Indeed, various modifications of the invention
in addition to those shown and described herein will become
apparent to those skilled in the art and are intended to fall
within the scope of the appended claims.
[2039] A number of references have been cited, the entire
disclosures of which are incorporated herein by reference.
* * * * *
References